(HETERO)ARYL SUBSTITUTED SULFONYL-2-(1H-PYRROLO[2,3-B]PYRIDINE-5-OXY) BENZAMIDE COMPOUNDS AND THEIR USE AS APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES

COMPOSES DE BENZAMIDE SULFONYL-2-(1H-PYRROLO[2,3-B]PYRIDINE-5-OXY) (HETERO)ARYLE SUBSTITUE ET LEUR UTILISATION COMME AGENTS INDUISANT L'APOPTOSE POUR LE TRAITEMENT DE CANCER ET DE MALADIES IMMUNES ET AUTOIMMUNES

English Abstract

Compounds of Formulas I and II which inhibit the activity of anti-apoptocic
Bcl-2
proteins, compositions containing the compounds and methods of treating
diseases during
which is expressed anti-apoptotic Bcl-2 protein. Formulas I and II are as
follow:
(see formula I) and (see formula II)
wherein the definitions for A1, B1, D1, E1, G1, L1, Y1, Z1, Z1A, Z2, Z2A and
Z3 are as
defined in the specification.

French Abstract

La présente invention concerne des composés inhibant l'activité de protéines Bcl-2 anti-apoptotiques, des compositions contenant lesdits composés et des méthodes de traitement de maladies durant lesquelles une protéine Bcl-2 anti-apoptotique est exprimée.

Claims

CLAIMS:
1. A compound having Formula (III) or Formula (IV):
Image
or a therapeutically acceptable salt thereof, wherein
R100, R101, R102, and R104 are independently R57A, R57, OR57, SR57, S(O)R57,
SO2R57,
C(O)R57, CO(O)R57, OC(O)R57, OC(O)OR57, NH2, NHR57, N(R57)2, NHC(O)R57,
NR57C(O)R57,
NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(C)NHR57,
NHC(O)N(R57)2, NR57C(O)NHR57, NR57C(O)N(R57)2, C(O)NH2, C(O)NHR57,
C(O)N(R57)2,
C(O)NHOH, C(O)NHOR57, C(O)NHSO2R57, C(O)NR57SO2R57, SO2NH2, SO2NHR57,
SO2N(R57)2,
C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, CI,
Br or I;
n is 0,1,2, or 3;
p is 0, 1, 2, 3, 4, 5, or 6;
626

q is 0,1,2, 3, 4, 5, or 6;
s is 0, 1, 2, 3, or 4;
A1 is N or C(A2);
A2 is H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, C(O)OR1, OC(O)R1, NHR1, N(R1)2,
C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NHC(O)NH2,
NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2, SO2NH2, SO2NHR1,
SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2, NR1SO2NHR1,
NR1SO2N(R1)2,
C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2, C(NH)NHR1, C(NH)N(R1)2,
NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI, Br, I, CN, NO2, N3, OH,
C(O)H,
CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A;
B1 is H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, C(O)OR1, OC(O)R1, NHR1, N(R1)2,
C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NHC(O)NH2,
NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2, SO2NH2, SO2NHR1,
SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2, NR1SO2NHR1,
NR1SO2N(R1)2,
C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2, C(NH)NHR1, C(NH)N(R1)2,
NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI, Br, I, CN, NO2, N3, OH,
C(O)H,
CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A;
D1 is H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, C(O)OR1, OC(O)R1, NHR1, N(R1)2,
C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NHC(O)NH2,
NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2, SO2NH2, SO2NHR1,
SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2, NR1SO2NHR1,
NR1SO2N(R1)2,
C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2, C(NH)NHR1, C(NH)N(R1)2,
NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI, Br, I, CN, NO2, N3, OH,
C(O)H,
CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A;
E1 is H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, C(O)OR1, OC(O)R1, NHR1, N(R1)2,
C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NHC(O)NH2,
NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2, SO2NH2, SO2NHR1,
SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2, NR1SO2NHR1,
NR1SO2N(R1)2,
627

C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2, C(NH)NHR1, C(NH)N(R1)2,
NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI, Br, I, CN, NO2, N3, OH,
C(O)H,
CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A; and
Y1 is H, CN, NO2, C(O)OH, F, CI, Br, I, CF3, OCF3, CF2CF3, OCF2CF3, R17, OR17,

C(O)R17, C(O)OR17, SR17, SO2R17, NH2, NHR17, N(R17)2, NHC(O)R17, C(O)NH2,
C(O)NHR17,
C(O)N(R17)2, NHS(O)R17 or NHSO2R17; or
E1 and Y1, together with the atoms to which they are attached, are benzene,
naphthylene,
heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
and
A2, B1, and D1 are independently H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1,
C(O)OR1,
OC(O)R1, NHR1, N(R1)2, C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1,
NR1C(O)OR1, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2,
SO2NH2, SO2NHR1, SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2,
NR1SO2NHR1, NR1SO2N(R1)2, C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2,
C(NH)NHR1, C(NH)N(R1)2, NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI,
Br, I,
CN, NO2, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)ORIA; or
Y1 and B1, together with the atoms to which they are attached, are benzene,
naphthylene,
heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
and
A2, D1, and E1 are independently H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1,
C(O)OR1,
OC(O)R1, NHR1, N(R1)2, C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1,
NR1C(O)OR1, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2,
SO2NH2, SO2NHR1, SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2,
NR1SO2NHR1, NR1SO2N(R1)2, C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2,
C(NH)NHR1, C(NH)N(R1)2, NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI,
Br, I,
CN, NO2, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A; or
A2 and B1, together with the atoms to which they are attached, are benzene,
naphthylene,
heteroarene cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
and

628


D1, E1, and Y1 are independently H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1,
C(O)OR1,
OC(O)R1, NHR1, N(R1)2, C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1,
NR1C(O)OR1, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2,
SO2NH2, SO2NHR1, SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2,
NR1SO2NHR1, NR1SO2N(R1)2, C(O)NHNOH, C(O)NHNOR1, C(O)NHSO2R1, C(NH)NH2,
C(NH)NHR1, C(NH)N(R1)2, NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, CI,
Br, I,
CN, NO2, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A; or
A2 and D1, together with the atoms to which they are attached, are benzene,
naphthalene,
heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
and
B1, E1, and Y1 are independently H, R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1,
C(O)OR1,
OC(O)R1, NHR1, N(R1)2, C(O)NHR1, C(O)N(R1)2, NHC(O)R1, NR1C(O)R1, NHC(O)OR1,
NR1C(O)OR1, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2,
SO2NH2, SO2NHR1, SO2N(R1)2, NHSO2R1, NR1SO2R1, NHSO2NHR1, NHSO2N(R1)2,
NR1SO2NHR1, NR1SO2N(R1)2, C(O)NHNOH, C(O)NHNOR1, C(O)NHSO21R1, C(NH)NH2,
C(NH)NHR1, C(NH)N(R1)2, NHSO2NHR1, NHSO2N(CH3)R1, N(CH3)SO2N(CH3)R1, F, Cl,
Br, I,
CN, NO2, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, C(O)NH2 or C(O)OR1A;
R1 is R2, R3, R4 or R5;
R1A is cycloalkyl, cycloalkenyl or cycloalkynyl;
R2 is phenyl, which is unfused or fused with R2A; R2A is benzene, heteroarene,
cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R3 is heteroaryl, which is unfused or fused with R3A; R3A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R4A; R4A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted
with one or
two or three substituents that are independently R6, NC(R6A)(R6B), R7, OR7,
SR7, S(O)R7, SO2R7,

629


NHR7, N(R7)2, C(O)R7, C(O)NH2, C(O)NHR7, C(O)N(R7)2, NHC(O)R7, NR7C(O)R7,
NHSO2R7,
NHC(O)OR7, SO2NH2, SO2NHR7, SO2N(R7)2, NHC(O)NH2, NHC(O)NHR7,
NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)NHR7, OH, (O),
C(O)OH, N3, CN, NH2, CF3, CF2CF3, F, Cl, Br or I;
R6 is C2-C5-spiroalkyl, each of which is unsubstituted or substituted with OH,
(O), N3, CN,
CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3) or N(CH3)2;
R6A and R6B are independently selected alkyl;
R7 is R8, R9, R10 or R11;
R8 is phenyl, which is unfused or fused with R8A; R8A is benzene, heteroarene,
cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R9 is heteroaryl, which is unfused or fused with R9A; R9A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R10A; R10A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R11 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or
substituted with one or
two or three substituents that are independently R12, OR12, SR12, S(O)R12,
SO2R12, C(O)R12,
CO(O)R12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12,
NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12,
NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12,
C(O)N(R12)2,
C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12,
SO2N(R12)2,
C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, CI,
Br or I;
R12 is R13, R14, R15 or R16;
R13 is phenyl, which is unfused or fused with R13A; R13A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

630

R14 is heteroaryl, which is unfused or fused with R14A; R14A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R15 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each
of which is
unfused or fused with R15A; R15A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R16 is alkyl, alkenyl or alkynyl;
R17 is R185 R195 R20 or R21;
R18 is phenyl, which is unfused or fused with R18A; R18A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R19 is heteroaryl, which is unfused or fused with R19A; R19A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R20 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each
of which is
unfused or fused with R20A; R20A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R21 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or
substituted with one or
two or three substituents that are independently R22, OR22, Sr22, S(O)R22,
SO2R22, C(O)R22,
CO(O)R22, OC(O)R22, OC(O)OR22, NH2, NHR22, N(R22) 2;
NHC(O)R22; NR22C(O)R22;
NHS(O)2R22, NR22S(O)2R22; NHC(O)OR22, NR22C(O)OR22, NHC(O)NH2, NHC(O)NHR22,
NHC(O)N(R22)2,
NR22C(O)NHR22, NR22C(O)N(R22)2, C(O)NH2, C(O)NHR22, C(O)N(R22)2,
C(O)NHOH, C(O)NHOR22, C(O)NHSO2R22, C(O)NR22SO2R
22, SO2NH2, SO2NHR22, SO2N(R22)2,
C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, CI,
Br or I;
R22 is R235 R24 or R25;
R23 is phenyl, which is unfused or fused with R23A; R23A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
631

R24 is heteroarene, which is unfused or fused with R24A; R24A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R25A; R25A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R103 is R68, OR68, SR68, S(O)R68, SO2R68, C(O)R68, CO(C)R68, OC(O)R68,
OC(O)OR68,
NH2, NHR68, N(R68)2, NHC(O)R68, NR68C(O)R68, NHS(O)2R68, NR68S(O)2R68,
NHC(O)OR68,
NR68C(O)OR68, NHC(O)NH2, NHC(O)NHR68, NHC(O)N(R68)2, NR68C(O)NHR68,
NR68C(O)N(R68)2, C(O)NH2, C(O)NHR68, C(O)N(R68)2, C(O)NHOH, C(O)NHOR68,
C(O)NHSO2R68, C(O)NR68SO2R68, SO2NH2, SO2NHR68, SO2N(R68)2, C(O)H, C(O)OH,
CNOH,
CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, CI, Br or I;
r is 0,1,2,3, or 4;
wherein the cyclic moieties represented by E1 and Y1 together, Y1 and B1
together, A2 and
B1 together, A2 and D1 together, R1A, R2, R2A, R3, R3A, R4, R4A, R6, R8, R8A,
R9, R9A, R10, R10A, R13,
R13A, R14, R14A, R15, R15A, R18, R18A, R19, R19A, R20, R20A, R23, R23A, R24,
R24A, R25, and R25A are
independently unsubstituted, substituted or further substituted with one or
two or three or four or
five substituents that are independently R57A, R57, OR57, SR57, S(O)R57,
SO2R57, C(O)R57,
CO(O)R57, OC(O)R57, OC(O)OR57, NH2, NHR57, N(R57)2, NHC(O)R57, NR57C(O)R57,
NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)NHR57,
NHC(O)N(R57)2, NR57C(O)NHR57, NR57C(O)N(R57)2, C(O)NH2, C(O)NHR57,
C(O)N(R57)2,
C(O)NHOH, C(O)NHOR57, C(O)NHSO2R57, C(O)NR57SO2R57, SO2NH2, SO2NHR57,
SO2N(R57)2,
C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, Cl,
Br or I;
R57A is spiroalkyl or heterospiroalkyl;
R57 is R58, R59, R60 or R61;
R58 is phenyl, which is unfused or fused with R58A; R58A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
632

R59 is heteroaryl, which is unfused or fused with R59A; R59A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R69 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R60A; R60A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R61 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or
substituted with one or
two or three substituents that are independently R62; OR62; SR62; S(O)R62;
SO2R62; C(O)R62;
CO(O)R62, OC(O)R62, OC(O)OR62, NH2, NHR62, N(R62)2, NHC(O)R62, NR62C(O)R62;
NHS(O)2R62, NR62S(O)2R62,NHC(O)OR62, NR62(O)OR62, NHC(O)NH2, NHC(O)NHR62,
NHC(O)N(R62)2, NR62C(O)NHR62; NR62C(O)N(R62)2,C(O)NH2, C(O)NHR62, C(O)N(R62)2,
C(O)NHOH, C(O)NHOR62, C(O)NHSO2R62,C(O)NR62SO2R62,SO2NH2, SO2NHR62,
SO2N(R62)2,
C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, CI,
Br or I;
R62 is R63, R64, R65 or R66;
R63 is phenyl, which is unfused or fused with R63A; R63A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R64 is heteroaryl, which is unfused or fused with R64A; R64A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R65A; R65A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R66 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or
substituted with one or
two or three substituents that are independently R67, OR67, SR67, S(O)R67,
SO2R67, C(O)R67,
CO(O)R67, OC(O)R67, OC(O)OR67, NH2, NHR67, N(R67)2, NHC(O)R67, NR67C(O)R67,
NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR67C(O)OR67, NHC(O)NH2, NHC(O)NHR67,
NHC(O)N(R67)2, NR67C(O)NHR67, NR67C(O)N(R67)2, C(O)NH2, C(O)NHR67,
C(O)N(R67)2,
C(O)NHOH, C(O)NHOR67, C(O)NHSO2R67, C(O)NR67SO2R67, SO2NH2, SO2NHR67,
SO2N(R67)2,
633

C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, Cl,
Br or I;
R67 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl,
heterocycloalkyl
or heterocycloalkenyl;
wherein the cyclic moieties represented by R57A, R58, R59, R60, R63, R64, R65,
and R67 are
unsubstituted or substituted with one or two or three or four substituents
that are independently
R68, OR68, SR68, S(O)R68, SO2R68, C(O)R68, CO(O)R68, OC(O)R68,OC(O)OR68, NH2,
NHR68,
N(R68)2, NHC(O)R68, NR68C(O)R68,NHS(O)2R68, NR68S(O)2R68,NHC(O)OR68,
NR68C(O)OR68,
NHC(O)NH2, NHC(O)NHR68, NHC(O)N(R68)2, NR68C(O)NHR68, NR68C(O)N(R68), C(O)NH2
C(O)NHR68, C(O)N(R68)2, C(O)NHOH, C(O)NHOR68, C(O)NHSO2R68, C(O)NR68SO2R68,
SO2NH2, SO2NHR68, SO2N(R68)2, C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3,
NO2,
CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;
R68 is R69, R70, R71 or R72;
R69 is phenyl, which is unfused or fused with R69A; R69A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R70 is heteroaryl, which is unfused or fused with R70A; R70A is benzene,
heteroarene,
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
of which is
unfused or fused with R71A; R71A is benzene, heteroarene, cycloalkane,
cycloalkene,
heterocycloalkane or heterocycloalkene;
R72 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or
substituted with one or
two or three substituents that are independently R73, OR73, SR73, S(O)R73,
SO2R73, C(O)R73,
CO(O)R73, OC(O)R73, OC(O)OR73, NH2, NHR73, N(R73)2, NHC(O)R73, NR73C(O)R73,
NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)NHR73,
NHC(O)N(R73)2, NR73C(O)NHR73, NR73C(O)N(R73)2, C(O)NH2, C(O)NHR73,
C(O)N(R73)2,
C(O)NHOH, C(O)NHOR73, C(O)NHSO2R73, C(O)NR73SO2R73, SO2NH2, SO2NHR73,
SO2N(R73)2,
634

C(O)H, C(O)OH, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3,
F, CI,
Br or I;
R73 is alkyl, alkenyl or alkynyl, phenyl, heteroaryl, cycloalkyl,
cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl; and
wherein the moieties represented by R69, R70, and R71 are unsubstituted or
substituted with
one or two or three or four substituents that are independently NH2, C(O)NH2,
C(O)NHOH,
SO2NH2, CF3, CF2CF3, C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, OCF3,
OCF2CF3, F,
CI, Br or I.
2. The compound or therapeutically acceptable salt of claim 1, wherein
n is 0, and R100 is absent;
A1 is N or C(A2);
A2 is H, F, Br, I or CI;
B1 is R1, OR1, NHR1, NHC(O)R1, F, Br, I or CI;
D1 is H, F, Br, I or CI;
E1 is H; and
Y1 is H, CN, NO2, F, CI, Br, I, CF3, R17, OR17, SR17, SO2R17 or C(O)NH2; or
Y1 and B1, together with the atoms to which they are attached, are benzene,
heteroarene or
heterocycloalkene; and
A2, D1 and E1 are each H;
R1 is R4 or R5;
R4 is cycloalkyl or heterocycloalkyl;

635

R5 is alkyl or alkynyl, each of which is unsubstituted or substituted with one
or two or three
of independently selected R7, OR7, NHR7, N(R7)2, CN, OH, F, CI, Br or I;
R7 is R8, R9, R10 or R11;
R8 is phenyl;
R9 is heteroaryl;
R10 is cycloalkyl, cycloalkenyl or heterocycloalkyl; each of which is unfused
or fused with
R10A, R10A is heteroarene;
R11 is alkyl, which is unsubstituted or substituted with one or two or three
of independently
selected R12, OR12or CF3;
R12 is R14 or R16;
R14 is heteroaryl;
R16 is alkyl;
R17 is alkyl or alkynyl, each of which is unsubstituted or substituted with
one or two or
three of independently selected R22, F, CI, Br or I;
R22 is heterocycloalkyl;
p, q, r, and s are each 0 and R101, R102, RM3 and R104 are each absent;
wherein the cyclic moieties represented by Y1 and B1 together, R4, R8, R10,
and R22 are
independently unsubstituted, substituted or further substituted with one or
two or three or four or
five substituents that are independently R57A, R57, OR57, SO2R57, C(O)R57,
CO(O)R57,
C(O)N(R57)2, NH2, NHR57, N(R57)2, NHC(O)R57, NHS(O)2R57, OH, CN, (O), F, CI,
Br or I;
R57A is spiroalkyl, or spiroheteroalkyl;
R57 is R58, R60 or R61;
636

R58 is phenyl;
R60 is cycloalkyl or heterocycloalkyl;
R61 is alkyl, which is unsubstituted or substituted with one or two or three
substituents that
are independently R62, OR62, N(R62)2, C(O)OH, CN, F, CI, Br and I;
R62 is R65 or R66;
R65 is cycloalkyl or heterocycloalkyl;
R66 is alkyl, which is unsubstituted or substituted with OR67;
R67 is alkyl;
wherein the cyclic moieties represented by R57A, R58, and R60 are
unsubstituted or
substituted with one or two or three or four substituents that are
independently R68, F, CI, Br and I;
R68 is R71 or R72;
R71 is heterocycloalkyl; and
R72 is alkyl, which is unsubstituted or substituted with one or two F.
637

3. The
compound or therapeutically acceptable salt of claim 1, wherein the compound
has
formula (III)
Image
wherein
n, p, r, and q are each 0, and R100, R101, R102 and R103 are each absent;
A1 is N or C(A2);
A2 is H, F, Br, I or Cl;
B1 is R1, OR1, NHR1, NHC(O)R1, F, Br, I or Cl;
D1 is H, F, Br, I or Cl;
E1 is H; and
Y1 is H, CN, NO2, F, Cl, Br, I, CF3, R17, OR17, SR17, SO2R17 or C(O)NH2; or
638

Y1 and B1, together with the atoms to which they are attached, are benzene,
heteroarene, or
heterocycloalkene; and
A2, D1, and E1 are each H;
R1 is R4 or R5;
R4 is cycloalkyl or heterocycloalkyl;
R5 is alkyl or alkynyl, each of which is unsubstituted or substituted with one
or two or three
substituents that are independently R7, OR7, NHR7, N(R7)2, CN, OH, F, Cl, Br
or I;
R7 is R8, R9, R10 or R11;
R8 is phenyl;
R9 is heteroaryl;
R10 is cycloalkyl, cycloalkenyl or heterocycloalkyl; each of which is unfused
or fused with
R10A;
R10A is heteroarene;
R11 is alkyl, which is unsubstituted or substituted with one or two or three
substituents that
are independently R12, OR12 and CF3;
R12 is R14 or R16;
R14 is heteroaryl;
R16 is alkyl;
R17 is alkyl or alkynyl, each of which is unsubstituted or substituted with
one or two or
three substituents that are independently R22, F, CI, Br or I;
R22 is heterocycloalkyl;

639

wherein the cyclic moieties represented by yl and B1 together, R4, R8, R10,
and R22 are
independently unsubstituted, substituted or further substituted with one or
two or three or four or
five substituents that are independently R57A, R57, OR57, SO2R57, C(O)R57,
CO(O)R57,
C(O)N(R57)2, NH2, NHR57, N(R57)2, NHC(O)R57, NHS(O)2R57, OH, CN, (O), F, Cl,
Br or I;
R57A is spiroalkyl or spiroheteroalkyl;
R57 is R58, R60 or R61;
R58 is phenyl;
R60 is cycloalkyl or heterocycloalkyl;
R61 is alkyl, which is unsubstituted or substituted with one or two or three
substituents that
are independently R62, OR62, NR62)2 , C(O)OH, CN, F, Cl, Br or I;
R62 is R65 or R66;
R65 is cycloalkyl or heterocycloalkyl;
R66 is alkyl, which is unsubstituted or substituted with OR67;
R67 is alkyl;
wherein the cyclic moieties represented by R57A, R58 and R60 are unsubstituted
or
substituted with one or two or three or four substituents that are
independently R68, F, Cl, Br or I;
R68 is R71 or R72;
R71 is heterocycloalkyl; and
R72 is alkyl, which is unsubstituted or substituted with one or two F.
4. The compound or therapeutically acceptable salt of claim 1, which is:
4- {4-[(4'-chloro- 1 , 1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl}-N-({ 3 -
nitro-4- [(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl 1 sulfonyl)-2-( 1H-pyrrolo [2 ,3 -b]pyridin-5-
yloxy)benzamide;
640

4- { 4- [(4'-chloro- 1,1 '-biphenyl-2-yl)methyl]piperazin- 1 -yl}-N-( { 4- [(3
-morpholin-4-
ylpropyl)amino]-3 -nitrophenyl} sulfonyl)-2-(1H-pyrrolo [2,3 -b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl}
piperazin- 1 -yl)-N-({ 3-nitro-4-
[(1 -tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl}piperazin-
1 -yl)-N-( {4-[(1 -
methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide ;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl}piperazin-
1 -yl)-N-( { 3 -nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide ;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -
yl]methyl}piperazin- 1 -yl)-N-( {4-[(4-
methylpiperazin- 1 -yl)amino]-3 -nitrophenyl} sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
Trans-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -en-1 -
yl]methyl}piperazin- 1 -yl)-N-( { 4-
[(4-morpholin-4-ylcyclohexyl)amino]-3 -nitrophenyl} sulfonyl)-2-(1H-pyrrolo
[2,3 -
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -
yl]methyl}piperazin- 1 -yl)-N-( { 4- [(2-
methoxyethyl)amino]-3 -nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -
yl]methyl}piperazin- 1 -yl)-N-[(3-nitro-4-
{ [(3 S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo
[2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl }
piperazin- 1 -yl)-N- { [4-(1,4-
dioxan-2-ylmethoxy)-3 -nitrophenyl] sulfonyl } -2-(1H-pyrrolo [2,3 -b]pyridin-
5-
yloxy)benzamide;

641

4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{ [(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo
[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-(2-
naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N4 { 4- [(2-
methoxyethyl)amino]-3- [(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-
pyrrolo [2,3-
IA pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-l-
yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)-N-( { 4- [(tetrahydro-2H-pyran-4-
ylmethyl)amino]-3-
[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{ [3-nitro-4-
(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl1-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1,4-
dioxan-2-ylmethyl)amino]-3-nitrophenyl} sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(2,2,2-trifluoroethyl)amino]phenyl } sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(3,3,3-trifluoropropyl)amino]phenyl } sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-

yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N4 { 4- [(2S)-
1,4-dioxan-2-ylmethoxy] -3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3-b]pyridin-
5-
yloxy)benzamide;
642

Cis-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-[(4- { [(4-
methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3 -
b]pyridin-
5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-( {4- [(2R)-
1,4-dioxan-2-ylmethoxy] -3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -b]pyridin-
5-
yloxy)benzamide;
Trans-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-[(4-
{ [(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo
[2,3-
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N- { [5-cyano-6-
(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl } -2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N4 {4-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy] -3 -nitrophenyl} sulfonyl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
N- { [3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl} sulfonyl1-4-
(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
Cis-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -
yl]methyl}piperazin- 1 -yl)-N-( {41(4-
morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N- { [5 -chloro-
6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3 -yl] sulfonyl1-2-(1H-pyrrolo [2,3-
b]pyridin-
5-yloxy)benzamide;
5-( { [4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-
4-
ylmethoxy)nicotinamide;
643


N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-
(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-cyano-6-
(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-
chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(2,2-
dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-
4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(3-
morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;

644


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({5-cyano-6-
[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-cyano-6-
(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-
(4-chlorophenyl)-
4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[2-(2-
methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-({4-
[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-
yl}sulfonyl)-4-(4-
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(2-
cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
Trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-
nitrophenyl]sulfonyl}-4-(4-
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(1-
methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;

645


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-
[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-ethynyl-
6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-oxo-3,4-
dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-cyano-6-
(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
tert-butyl 3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-
nitrophenoxy]methyl}morpholine-4-carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-
(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-

yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[1-
(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

646


N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({5-cyano-6-
[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-
isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;.
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({1-[2-
fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-
yl}sulfonyl)-4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[1-(2,2-
difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;

647


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(1-
morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-[(4-
{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-
(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({5-cyano-6-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1,1-
dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-
4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

648

Trans-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}
piperazin-1-yl)-N-( {5-
cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl } sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-cyano-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl } sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-1-
yl)-N-[(4-
{ [(1S ,3R)-3-morpholin-4-ylcyclopentyl] amino } -3-nitrophenyl)sulfonyl]-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-[(4-
{ [(1R,3S)-3-morpholin-4-ylcyclopentyl]amino } -3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-1-
yl)-N-( {4-
[(morpholin-2-ylmethyl)amino]-3-nitrophenyl sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl }piperazin-1-
yl)-N-({3-nitro-4-
[(tetrahydrofuran-3-ylmethyl)amino]phenyl } sulfonyl)-2-(1H-pyrrolo [2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-1-
yl)-N- { [4-({1-[cis-
3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl} amino)-3-nitrophenyl]
sulfonyl }-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-1-
yl)-N-({3-nitro-4-
[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl } sulfonyl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl} sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-
5-yloxy)benzamide;

649


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[3-nitro-4-
({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-
yl]methyl}amino)phenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide;
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide;
Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
1-yl)-N-[(4-{[4-
(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-

b]pyridin-5-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-[(3-
nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl} sulfonyl)-4-
(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-({4-
[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
tert-butyl 4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-
nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;

650


Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-[(3-
nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-
yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({1-[2-
fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3R)-
1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-
nitrophenyl)sulfonyl]-
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3S)-1-
(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-
nitrophenyl)sulfonyl]-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(4-
methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-(2-
methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

651

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl }
piperazin- 1 -yl)-N-[(4- { [trans-
4-(fluoromethyl)-1 -oxetan-3-ylpyrrolidin-3-yl]methoxy} -3 -
nitrophenyl)sulfonyl]-2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl}piperazin-
1-yl)-N- [(4- { [(4-
fluorotetrahydro-2H-pyran-4-yl)methyl]amino } -3 -nitrophenyl)sulfonyl] -2-( 1
H-pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1 -yl]methyl }
piperazin- 1 -yl)-N-( {3 -nitro-4-
[(1 -oxetan-3 -ylpiperidin-4-yl)amino]phenyl } sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1 -yl]methyl 1
piperazin- 1 -yl)-N-( {4-[(1 -
cyclobutylpiperidin-4-yl)amino]-3 -nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl 1
piperazin- 1-yl)-N- [(4- { [1 -(2,2-
dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3 -
nitrophenyl)sulfonyl]-2-(1 H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl
}piperazin-1 -yl)-N- [(4- { [(3 S)- 1 -
cyclopropylpyrrolidin-3 -yl]amino}-3 -nitrophenyl)sulfonyl] -2-(1H-pyrrolo
[2,3 -b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl }
piperazin-1 -yl)-N-( { 3 -nitro-4-
[(1 -tetrahydrofuran-3 -ylpiperidin-4-yl)amino]phenyl } sulfonyl)-2-(1 H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl}piperazin-
1 -yl)-N-[(4- { [(3R)-
1 -cyclopropylpyrrolidin-3 -yl]amino}-3 -nitrophenyl)sulfonyl]-2-(1H-pyrrolo
[2,3 -b]pyridin-
-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl] methyl }
piperazin- 1 -yl)-N- { [3 -nitro-4-
( { [(3 S)-1 -tetrahydro-2H-pyran-4-ylpyrrolidin-3 -
yl]methyl}amino)phenyl]sulfonyl } -2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;

652


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(3-
hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[1-
(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
(4-chlorophenyl)-
4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3R)-
1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({1-[2-
fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[1-
(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
(4-chlorophenyl)-
4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(3-
methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;

653


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-
({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-n]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-
({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-
({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-
({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[({1-[2-
fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-
nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-

b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(1-
cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

654


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-(2-
fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-
(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(2S)-
4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxyl-3-nitrophenyl)sulfonyl]-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(4-
cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-({4-[({1-[2-
fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-
nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

655


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(3-
methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[4-
(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-(1,4-
dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3R)-
1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3S)-1-
(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3S)-1-
(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

656


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3R)-
1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-

b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(3-
hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[3-
(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[cis-3-
morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-{[4-
({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-
2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;

657

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -
yl]methyl}piperazin- 1 -yl)-N-( { 4-[(4-
fluoro- 1 -tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-
nitrophenyl}sulfonyl)-2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl}
piperazin- 1 -yl)-N-( {4-[(4-
fluoro-1 -tetrahydrofuran-3 -ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-
2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl} piperazin-
1 -yl)-N-[(4- { [4-
fluoro- 1 -(methylsulfonyl)piperidin-4-yl]methoxy} -3 -nitrophenyl)sulfonyl]-2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl}
piperazin- 1 -yl)-N- { [3-nitro-4-
({ [(3R)-1-oxetan-3 -ylpyrrolidin-3-yl]methyl} amino)phenyl]sulfonyl}-2-(1 H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
Trans-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl}
piperazin-1 -yl)-N-( {4-
[(4-hydroxycyclohexyl)methoxy]-3 -nitrophenyl } sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl }
piperazin- 1 -yl)-N- { [4-( {4-[3 -
(dimethylamino)propoxy]benzyl } amino)-3 -nitrophenyl]sulfonyl}-2-(1H-pyrrolo
[2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl }piperazin-1-
yl)-N-[(4-{ [4-(2-
morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3 -

b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl }
piperazin-1 -yl)-N- { [4-( { [(E)-
4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo [2,3
-
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl]methyl }
piperazin- 1 -yl)-N- { [4-( { [(Z)-4-
hydroxy- 1 -adamantyl]methyl}amino)-3 -nitrophenyl] sulfonyl } -2-(1H-pyrrolo
[2,3 -
b]pyridin-5 -yloxy)benzamide;

658

N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyllsulfonyl)-4-
(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-
{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-
nitrophenyl)sulfonyl]-
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-
{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-
nitrophenyl)sulfonyl]-
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({(3R)-
1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl)amino)-3-
nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[6-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-
yl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[3-nitro-4-
({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-
{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide ;
659

Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-
{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[({4-[2-
(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-
(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-
(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-

pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
(2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-
nitrophenyl)amino]methyl}morpholin-4-yl)acetic acid;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[3-nitro-4-
({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(4-
cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[5-
(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl)sulfonyl}-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
660

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-
[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
ethyl 4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-
1-
carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[4-
(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-nitro-4-
{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-

b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(3R)-
1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-
[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(1-
isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-
5-
yloxy)benzamide;
661

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N- { [4-( { [1-(2-
methoxyethyl)piperidin-3-yl]methyl}amino)-3 -nitrophenyl]sulfonyl}-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N- { [4-({ [1-
(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl] sulfonyl}-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-( {4-[(4-
fluoro-1-methylpiperidin-4-yl)methoxy] -3-
[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-
(1H-pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]
amino}pyridine-3-yl)sulfonyl] -4-
(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1-
yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
tert-butyl 4-[(4- {[4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl} piperazin-1-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-
nitrophenyl)amino]piperazine-1-carboxylate;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-( { 3-
(pentafluoro-.lambda.6-sulfanyl)-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)-2-
(1H-pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en-1 -yl]methyl
}piperazin-1-yl)-N-( { 4- [(4-
methoxytetrahydro-2H-pyran-4-yl)methoxy] -3-nitrophenyl } sulfonyl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-[(4- { [(3R)-
1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxyl-3 -nitrophenyl)sulfonyl] -2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
662

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl}piperazin-
1-yl)-N-[(3 -nitro-4-
{ [4-(oxetan-3 -yl)piperazin- 1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl] methyl}piperazin-
1-yl)-N- [(3 -nitro-4-
{ [4-(tetrahydro-2H-pyran-4-yl)piperazin- 1-yl] amino}phenyl)sulfonyl] -2-( 1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N-( { 3 -nitro-4-
[(3R-tetrahydrofuran-3 -ylamino]phenyl}sulfonyl)-2-( 1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl }
piperazin- 1-yl)-N-[(4- { [(4,4-
difluorocyclohexyl)methyl]amino 1-3 -nitrophenyl)sulfonyl] -2-( 1H-pyrrolo
[2,3 -b]pyridin-5-
yloxy)benzamide;
N-( {4- [( 1-tert-butylpiperidin-4-yl)amino] -3 -
[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl}piperazin- 1-yl)-2-(
1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl] methyl }
piperazin- 1-yl)-N-({4-( { [4-
(oxetan-3 -yl)morpholin-2-yl] methyl } amino)-3-
[(trifluoromethyl)sulfonyl]phenyl} sulfonyl)-2-( 1H-pyrrolo [2,3 -b]pyridin-5-
yloxy)benzamide;
N-[(5-chloro-6- { [(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3 -
yl)sulfonyl]-4-(4-
{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-
2-( 1H-
pyrrolo [2,3 -b]pyridin-5 -yloxy)benzamide;
N-( { 5-chloro-6-[( 1-cyclopropylpiperidin-4-yl)amino]pyridin-3 -yl}sulfonyl)-
4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-2-( 1H-
pyrrolo [2,3 -
b]pyridin-5 -yloxy)benzamide ;
663

N-[(5-chloro-6- { [(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl} methyl} piperazin-1-yl)-2-(1H-

pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy} pyridin-
3-yl)sulfonyl] -4-
(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-
yl)sulfonyl] -4-
(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo[2,3-1b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-
1-yl)-N-( {5-fluoro-
6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
N-(15-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}
sulfonyl)-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl }piperazin-1-yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-( {6-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo
[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl }piperazin-1-
yl)-N- { [4-( { [4-
(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl] sulfonyl}-
2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
664

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl }
piperazin- 1-yl)-N- { [4-( { (3 R)-
1- [2-(2-methoxyethoxy)ethyl]pyrrolidin-3 -yl) amino)-3 -nitrophenyl]
sulfonyl}-2-( 1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl }
piperazin- 1-yl)-N- [(4- { [(3 R)-
1-(N,N-dimethylglycyl)pyrrolidin-3 -yl]amino 1-3 -nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl } piperazin-
1-yl)-N- [(3 -nitro-4-
{ [ 1-(oxetan-3 -yl)azetidin-3 -yl] amino }phenyl)sulfonyl] -2-( 1H-pyrrolo
[2,3 -b]pyridin-5-
yloxy)benzamide;
N-[(5-chloro-6- { [1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4-
{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl } piperazin- 1-
yl)-2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl }
piperazin- 1-yl)-N- { [4-( { [(2R)-
4-(N,N-dimethylglycyl)morpholin-2-yl]methyl} amino)-3 -nitrophenyl] sulfonyl}-
2-( 1H-
pyrrolo [2,3 -b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N- { [4-( { [(2S)-
4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3 -nitrophenyl] sulfonyl}-2-
(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-
yl)sulfonyl}-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl } piperazin- 1-yl)-2-(
1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(3R)- 1-(2,2-difluoroethyl)pyrrolidin-3 -yl] oxy} pyridin-3
-yl)sulfonyl]-4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-2-( 1H-
pyrrolo [2,3 -
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N-[(4- { [(3R)-
1-(cyanomethyl)pyrrolidin-3 -yl]amino1-3 -nitrophenyl)sulfonyl] -2-( 1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide ;
665

N-( { 5-chloro-6- [(4-fluoro- 1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}
sulfonyl)-4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en- 1-yl]methyl} piperazin- 1-yl)-2-( 1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxyl
pyridin-3-yl)sulfonyl]-
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxyl
pyridin-3-yl)sulfonyl]-4-(4-
{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-1-yl)-
2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl}piperazin-
1-yl)-N-( { 3-nitro-4-
[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo [2,3-
b]pyridin-5 -
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl} piperazin-
1-yl)-N-[(4- { [(trans-
4-cyanocyclohexyl)methyl] amino } -3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3-
b]pyridin-5-
yloxy)benzamide;
N-[(5-chloro-6- { [4-fluoro- 1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4- { [2-
(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl} piperazin-1-yl)-2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl} piperazin-
1-yl)-N-({ 5-cyano-6-
[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo [2,3-
b]pyridin-
5-yloxy)benzamide ;
4-[4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl } piperazin-
1-yl)-N- { [4-(3-
furylmethoxy)-3-nitrophenyl] sulfonyl}-2-(1H-pyrrolo [2,3-b]pyridin-5 -
yloxy)benzamide;
N-[(5-chloro-6- { [(3R)- 1-( 1,3-difluoropropan-2-yl)pyrrolidin-3-
yl]methoxy}pyridin-3-yl)sulfonyl]-
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl}piperazin-
1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5 -yloxy)benzamide;
666

N-[(5-chloro-6- { [(3R)- 1-(2,2-difluoroethyl)pyrrolidin-3 -yl]methoxyl
pyridin-3 -yl)sulfonyl]-4-(4-
{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-
2-(1H-
pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6- { [ 1-(1,3 -difluoropropan-2-yl)-4-fluoropiperidin-4-
yl]methoxy}pyridin-3 -
yl)sulfonyl]-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-
yl]methyl } piperazin-
1-yl)-2-(1H-pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
N-( {3 -chloro-4- [(4-fluoro- 1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-
4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-2-(1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N- { [3 -cyano-4-
(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
N-[(5-chloro-6- { [1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}
pyridin-3 -yl)sulfonyl] -4-
(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-
yl)-2-(1H-
pyrrolo [2,3 -b]pyridin-5 -yloxy)benzamide;
N-( {3 -chloro-4- [(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl } piperazin- 1-yl)-2-(
1H-pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
N-( {5 -chloro-6- [(4,4-difluorocyclohexyl)methoxy]pyridin-3 -yl} sulfonyl)-4-
(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin- 1-yl)-2-( 1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N- { [6- { [1-(1,3 -
difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxyl-5 -
(trifluoromethyl)pyridin-3 -
yl] sulfonyl } -2-( 1H-pyrrolo [2,3 -b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N-( { 5-chloro-
6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3 -yl}sulfonyl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
667

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en-1-yl]methyl } -3 -
methylpiperazin-1-yl)-N-
({ 3 -nitro-4- [(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)-24 1H-
pyrrolo [2,3 -
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl} piperazin-
1-yl)-N-[(4- { [3 -
(cyclopropylamino)propyl]amino } -3 -nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
N- { [5-chloro-6-(2-methoxyethoxy)pyridin-3 -yl] sulfonyl}-4-(4- { [2-(4-
chlorophenyl)-4,4-
dimethylcyclohex- 1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-N- { [5 -fluoro-
6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3 -yl]sulfonyl } -2-(1H-pyrrolo
[2,3 -b]pyridin-
-yloxy)benzamide;
N-[(3 -chloro-4- { [1-(methoxyacetyl)piperidin-4-yl]methoxylphenyl)sulfonyl] -
4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en- 1-yl]methyl } piperazin-1-yl)-2-( 1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
N-[(3 -chloro-4- { [1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}
phenyl)sulfonyl]-4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3 -
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl}piperazin-
1-yl)-2-(1H-
pyrrolo [2,3 -b]pyridin-5 -yloxy)-N- { [6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-
(trifluoromethyl)pyridin-3 -yl} sulfonyl } benzamide;
N-({ 5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3 -yl} sulfonyl)-4-
(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl} piperazin-1-yl)-2-(1H-
pyrrolo[2,3 -
b] pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1-yl]methyl} piperazin-
1-yl)-N-({ 3 -cyano-4-
[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl } sulfonyl)-2-(1H-pyrrolo
[2,3 -
b]pyridin-5-yloxy)benzamide;
668

4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({6- [(trans-
4-methoxycyclohexyl)methoxy] -5-(trifluoromethyl)pyridin-3 -yl}sulfonyl)-2-(1H-

pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-
1-yl)-N-( {6-[(cis-4-
methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(3-chloro-4- { [trans-4-(morpholin-4-yl)cyclohexyl]methoxylphenyl)sulfonyl]-
4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-
1-yl)-N- { [4-( {3-
[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]
sulfonyl}-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-( {3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4- {
[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl] methyl } piperazin-
1-yl)-N-( {3-chloro-
4- [(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl } piperazin-
1-yl)-N-( {4- [(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N- { [4-( {3-
[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl] sulfonyl}-
2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(3-chloro-4- { [1-(oxetan-3-yl)piperidin-4-yl]methoxy} phenyl)sulfonyl]-4-
(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl 1 piperazin-1-yl)-2-(1 H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;

669


4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3,5-
difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({3-
[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-
4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3,4-
difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-
yl)sulfonyl]-4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
methyl 2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-
nitrophenyl)amino]methyl}morpholine-4-carboxylate;
2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-
nitrophenyl)amino]methyl}-N-
ethyl-N-methylmorpholine-4-carboxamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[4-
(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({3-
[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;

670


N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-
yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[3-chloro-
4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[(2R)-
4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({[(2S)-
4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-
yl]sulfonyl}-
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-
(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-
(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-
N-
ethyl-N-methylmorpholine-4-carboxamide;
(2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-

671


yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-
carboxamide;
N-[(5-chloro-6-{ [(4-cyclopropylmorpholin-2-yl)methyl]aminolpyridin-3-
yl)sulfonyl]-4-(4-{ [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
2-{ [(3-chloro-5-{ [4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl} piperazin-1-yl)-2-(1H-pyrrolo [2,3-b]pyridin-5-yloxy)benzoyl]
sulfamoyl}pyridin-2-yl)amino]methyl}-
N-ethyl-N-methylmorpholine-4-carboxamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl}methyl}piperazin-1-
yl)-N-[(4-{ [(trans-
4-hydroxy-4-methylcyclohexyl)methyl] amino 1-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-[(4-{ [(cis-4-
hydroxy-4-methylcyclohexyl)methyl] amino 1-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{ [(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo [2.2. 1 ]hept-2-
yl]methoxylpyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-yl]methyl} piperazin-
1-yl)-2-(1H-pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{ [4-({4-[(2-
cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl1-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{ [5-chloro-
6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl] sulfonyl1-
2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{ [(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo [2.2. 1 ]hept-2-
yl]methoxylpyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-
dimethylcyclohex-1-en-1-yl]methyl} piperazin-
1-yl)-2-(1 H-pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
672


4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-( {4-[(cis-4-
hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-[(4-{ [4-(3 ,3-difluoropyrrolidin-1-yl)cyclohexyl] amino 1-3-
nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
N-( { 5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl1
sulfonyl)-4-(4-{ [2-
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-( {5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-
yl}sulfonyl)-4-(4-{ [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-( 1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{ [4-( {4-
[(2,2-difluorocyclopropyl)amino] cyclohexyl} amino)-3-nitrophenyl]sulfonyl1-2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-( { 5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}
sulfonyl)-4-(4-{ [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{ [3-nitro-4-
(2-oxaspiro [3.5]non-7-ylmethoxy)phenyl] sulfonyl1-2-(1H-pyrrolo [2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-( { 4-[(trans-
4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl} sulfonyl)-2-(1H-pyrrolo
[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-
yl)-N-( {4-[(4-
cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyllsulfonyl)-2-(1H-pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
673

N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-
yl}sulfonyl)-4-
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-
2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-
yl)sulfonyl)-4-
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-
2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(3-cyano-4-
{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(trans-
4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(cis-4-
ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[3-nitro-4-
({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy] phenyl} sulfonyl)-
4-(4-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-{[4-({4-[(2-
cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-
nitrophenyl]sulfonyl}-2-
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyllpiperazin-1-
yl)-N-({5-nitro-6-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
674

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(4-{[(4-
cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-
[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(6-{[(trans-
4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-

pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(5-cyano-6-
{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-
carboxamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyllpiperazin-1-
yl)-N-{[4-({[4-
(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(5-chloro-6-
{[1-(1,3-thiazol-2-yl)piperidin-4-yl] methoxy}pyridin-3-yl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide; or
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-[(6-{[(cis-4-
hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
675

or a therapeutically acceptable salt thereof.
5. A compound or a therapeutically acceptable salt thereof, wherein the
compound is 4-(4-
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-
({3-nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide.
6. A compound or a therapeutically acceptable salt thereof, wherein the
compound is 4-(4-
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-
[(4-{[(trans-4-
hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide.
7. A compound or therapeutically acceptable salt thereof, wherein the
compound is
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-({3-
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-({4-
[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}
piperazin-1-yl)-N-{[4-
(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-

yloxy)benzamide;
Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-
N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-{[5-
cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
676

4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-{[5-
chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-

(trifluoromethyl)phenyl]sulfonyl}benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-

[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-
N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-
[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-({4-
[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-
2-(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-
({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-({4-
[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-
N-({4-[(4-
morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
677

Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl]methyl}piperazin-1-yl)-N-
[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-
[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-
N-[(4-{[(4-
methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-
b]pyridin-
5-yloxy)benzamide;
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-
nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({4-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-N-({3-nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-
1-yl)-N-({3-
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide;
678

4- { 4- [(4'-chlorobiphenyl-2-yl)methyl] -4-methoxypiperidin-1-yl}-N-( {5-
chloro-6-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo
[2,3-
b]pyridin-5-yloxy)benzamide;
4- {4- [(4'-chlorobiphenyl-2-yl)methyl] -4-methoxypiperidin-1-yl}-N-( {3-nitro-
4-[(tetrahydro-2H-
pyran-4-ylmethyl)amino]phenyl} sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4-(4- { [9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro [5.5]undec-
8-en-8-
yl]methyl} piperazin-1-yl)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo [2,3-b]pyridin-5-
yloxy)benzamide;
4-(4- { [9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-
yl]methyl}piperazin-1-yl)-N-
( {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-
en-8-
yl]methyl}piperazin-1-yl)-N- { [5-chloro-6-(tetrahydro-2H-pyran-4-
ylmethoxy)pyridin-3-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4- { [9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-
yl}methyl}piperazin-1-yl)-N-
{ [5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl } -2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4- {4- [(4'-chlorobiphenyl-2-yl)methyl] -4-fluoropiperidin- 1 -yl}-N-( {3 -
nitro-4-[(tetrahydro-2H-
pyran-4-ylmethyl)amino]phenyl} sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide;
4- {4- [(4'-chlorobiphenyl-2-yl)methyl] -4-fluoropiperidin-1-yl}-N-( { 5-
chloro-6-[(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo
[2,3-
b]pyridin-5-yloxy)benzamide;
4-(4- { [9-(4-chlorophenyl)-3-isopropyl-3-azaspiro [5.5]undec-8-en-8-
yl]methyl}piperazin-1-yl)-2-
(1H-pyrrolo [2,3-b]pyridin-5-yloxy)-N-( {4- [(tetrahydro-2H-pyran-4-
ylmethyl)amino]-3-
(trifluoromethyl)phenyl}sulfonyl)benzamide;
679

Trans-4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1 -
yl)-N-( {3 -nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)-2-(1 H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3 -yl}
sulfonyl)-4-(4- { [2-(4-
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-( 1 H-
pyrrolo [2,3 -
b]pyridin-5 -yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperidin-1-
yl)-N-( { 3 -nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl } sulfonyl)-2-(1 H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1 -yl]methyl} piperidin-
1-yl)-N- { [3 -chloro-
4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-5,5 -difluorocyclohex-1-en-1 -yl]methyl}piperazin-
1-yl)-N-( { 3-nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1 H-pyrrolo [2,3 -
b]pyridin-5-
yloxy)benzamide;
4-(4- { [2-(4-chlorophenyl)-5,5-difluorocyclohex-1 -en-1-yl]methyl}piperazin-1-
yl)-N-[(4- { [(trans-
4-hydroxycyclohexyl)methyl]amino }-3 -nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3-
b]pyridin-
5-yloxy)benzamide;
N-( {3 -chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-
(4- { [9-(4-
chlorophenyl)-3 -(oxetan-3 -yl)-3 -azaspiro [5 .5 ]undec-8-en-8-yl]methyl }
piperazin-1-yl)-2-
(1 H-pyrrolo [2,3 -b]pyridin-5 -yloxy)benzamide;
4-(4- { [5-(4-chlorophenyl)spiro [2 .5]oct-5 -en-6-yl]methyl}piperazin-1-yl)-N-
( { 3 -nitro-4-
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl }sulfonyl)-2-(1 H-pyrrolo [2,3 -
b]pyridin-5 -
yloxy)benzamide;
4-(4- { [5-(4-chlorophenyl)spiro [2. 5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-
[(4- { [(4-
cyclopropylmorpholin-2-yl)methyl]amino}-3 -nitrophenyl)sulfonyl]-2-(1H-pyrrolo
[2,3 -
b]pyridin-5-yloxy)benzamide;

680


N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-
yl}sulfonyl)-4-(4-{[5-
(4-chlorophenyl)spiro [2 .5 ]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxyl pyridin-3-
yl)sulfonyl]-4-(4-{[5-
(4-chlorophenyl)spiro [2 .5 ]oct-5-en-6-yl] methyl}piperazin-1-yl)-2-(1H-
pyrrolo [2,3-
b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5 ,5-bis(fluoromethyl)cyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-({3-
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo
[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-
yl}methyl}piperazin-l-
yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-l-
yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-
yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl pivalate;
{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
yl)-2-(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-
yl)methoxy]-
3-nitrophenyl}sulfonyl)amino}methyl butyrate;
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]
methyl}piperazin-1-yl)-N-[(4-
{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino1-3-nitrophenyl)sulfonyl]-2-
(1H-
pyrrolo [2,3-b]pyridin-5-yloxy)benzamide; or
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl1 sulfonyl)-2-(1H-pyrrolo [2,3-b]pyridin-5-yloxy)
benzamide.
8. A compound which is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-
1-
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo [2,3-b]pyridin-5-
yloxy)benzamide.
68 1


9. A compound which is 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-

yl] methyl}piperazin-1-yl)-N-[(4-[(trans-4-hydroxy-4-methyl cyclohexyl)methyl]
amino-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo [2,3-1)] pyridin-5-
yloxy)benzamide.
10. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, colorectal
cancer, esophageal cancer, hepatocellular cancer, melanoma, myelogenous
leukemia, oral cancer,
ovarian cancer, non-small cell lung cancer, prostate cancer or small cell lung
cancer in a patient.
11. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
chronic lymphocytic leukemia in a patient.
12. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
a lymphoid malignancy of T-cell or B-cell origin in a patient.
13. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
lymphoblastic leukemia in a patient.
14. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
follicular lymphoma in a patient.
15. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
myeloma in a patient.
16. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use in treating
spleen cancer in a patient.
17. The compound or therapeutically acceptable salt of any one of claims 1-
9 for use as a
medicament.
18. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, colorectal
cancer, esophageal cancer, hepatocellular cancer, melanoma, myelogenous
leukemia, oral cancer,
ovarian cancer, non-small cell lung cancer, prostate cancer or small cell lung
cancer in a patient.
682


19. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
chronic lymphocytic leukemia in a patient.
20. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
a lymphoid malignancy of T-cell or B-cell origin in a patient.
21. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
lymphoblastic leukemia in a patient.
22. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
follicular lymphoma in a patient.
23. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
myeloma in a patient.
24. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for treating
spleen cancer in a patient.
25. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating bladder cancer, brain cancer, breast
cancer, bone marrow
cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular
cancer, melanoma,
myelogenous leukemia, oral cancer, ovarian cancer, non-small cell lung cancer,
prostate cancer or
small cell lung cancer in a patient.
26. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating chronic lymphocytic leukemia in a
patient.
27. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating a lymphoid malignancy of T-cell or B-
cell origin in a
patient.
28. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating lymphoblastic leukemia in a patient.
683

29. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating follicular lymphoma in a patient.
30. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating myeloma in a patient.
31. Use of the compound or therapeutically acceptable salt of any one of
claims 1-9 for the
manufacture of a medicament for treating spleen cancer in a patient.
684

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME 2 DE 3
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
THIS IS VOLUME 2 OF 3
NOTE: For additional volumes please contact the Canadian Patent Office.

CA 02759182 2011-10-18
WO 2010/138588
PCT/US2010/036198
121 < 0.000010 311 < 0.000010
122 < 0.000010 312 < 0.000010
123 < 0.000010 313 0.001102
124 < 0.000010 314 0.000042
125 < 0.000010 315 0.000052
126 < 0.000010 316 0.000601
127 < 0.000010 317 < 0.000010
128 < 0.000010 318 < 0.000010
129 0.000002 319 < 0.000010
130 < 0.000010 320 < 0.000010
131 < 0.000010 321 < 0.000010
132 < 0.000010 322 < 0.000010
133 < 0.000010 323 0.000104
134 < 0.000010 324 < 0.000010
135 < 0.000010 325 < 0.000010
136 < 0.000010 326 < 0.000010
137 < 0.000010 327 < 0.000010
138 < 0.000010 328 < 0.000010
139 < 0.000010 329 0.000030
140 < 0.000010 330 < 0.000010
141 < 0.000010 331 0.001086
142 0.00013 332 0.000621
143 < 0.000010 333 0.000511
144 < 0.000010 334 0.000572
145 < 0.000010 335 0.000150
146 < 0.000010 336 0.000198
147 < 0.000010 337 < 0.000010
148 < 0.000010 338 0.000013
149 < 0.000010 339 0.000036
150 < 0.000010 340 < 0.000010
151 0.000017 341 < 0.000010
152 < 0.000010 342 < 0.000010
- 249 -

CA 02759182 2011-10-18
WO 2010/138588
PCT/US2010/036198
153 < 0.000010 343 < 0.000010
154 < 0.000010 344 < 0.000010
155 0.000059 345 < 0.000010
156 < 0.000010 346 0.000042
157 < 0.000010 347 0.000013
158 < 0.000010 348 0.000034
159 < 0.000010 349 0.000023
160 < 0.000010 350 < 0.000010
161 < 0.000010 351 < 0.000010
162 < 0.000010 352 0.000014
163 < 0.000010 353 < 0.000010
164 < 0.000010 354 0.000010
165 < 0.000010 355 0.000014
166 < 0.000010 356 0.000039
167 < 0.000010 357 < 0.000010
168 < 0.000010 358 < 0.000010
169 0.000021 359 < 0.000010
170 0.000022 360 < 0.000010
171 < 0.000010 361 < 0.000010
172 < 0.000010 362 0.000016
173 < 0.000010 363 0.000017
174 < 0.000010 364 < 0.000010
175 0.000119 365 < 0.000010
176 0.000023 366 0.000024
177 0.000111 367 nd
178 0.000076 368 nd
179 < 0.000010 369 < 0.000010
180 < 0.000010 370 0.000285
181 0.000017 371 < 0.0000010
182 0.000068 372 nd
183 < 0.000010 373 < 0.0000010
184 < 0.000010 374 < 0.0000010
- 250 -

CA 02759182 2015-04-17
185 0.000022 375 0.00010999
186 0.000047 376 <:0.0000010
187 0.00008 377 <:0.0000010
188 - <:0.000010 378 <0.0000010
189 0.000018
nd = not detemiined
The inhibition constant (Ki) is the dissociation constant of an enzyme-
inhibitor complex or a
protein/small molecule complex, wherein the small molecule is inhibiting
binding of one
protein to another protein or peptide. So a large Ki value indicates a low
binding affinity and
a small IC; value indicates a high binding affinity.
TABLE 2 shows inhibition constants for the inhibition of a Bak BH3 peptide
probe to
Bc1-2 protein and indicate that compounds according to the invention have high
binding
affinities for anti-apoptotic Bc1-2 protein. The compounds are therefore
expected to have
utility in treatment of diseases during which anti-apoptotic Bc1-2 protein is
expressed.
RS4;11 Cell Viability Assay
The acute lymphoblastic leukemia (ALL) cell line RS4;11 was used as the
primary
human cell line to assess the cellular activity of Bc1-2 selective agents in
vitro and their
efficacy in vivo. Previous studies have shown by BH3 profiling, a
mitochondrial assay that
classifies blocks in the intrinsic apoptotic pathway, that RS4;11 cells were
highly dependant
on BCL-2 for survival and sensitive to the Bc1-2 family member inhibitor ABT-
737 (Blood,
2008, Vol. 111, 2300-2309). The prevalence of Bc1-2 complexed to the
proapoptotic BH3
protein Bim in RS4;11 suggests that these cells are "primed" or more
susceptible to cell death
by antagonism of the antiapoptotic protein Bc1-2 for which they depend on for
survival.
RS4;11 cells were cultured in RPMI-1640 supplemented with 2 mM L-glutamine,
TM
10% FBS, 1 mM sodium pyruvate, 2 mM HEPES, 1% penicillin/streptomycin
(Invitrogen),
4.5 g/L glucose and maintained at 37 C containing 5% CO2. To test for the
cellular activity
of compounds in vitro, cells were treated at 50,000 cells per well in 96-well
microtiter plates
in the presence of 10% human serum for 48 hours in a humidified chamber with
5% CO2.
TM
Cell cytotoxicity EC50 values were assessed using CellTiter Glo (Promega)
according to the
manufacturer's recommendations. The EC50 values were determined as a
percentage of
viable cells following treatment compared to the untreated control cells.
Table 3. RS4;11 EC50 Values (PM)
- 251 -

CA 02759182 2011-10-18
WO 2010/138588
PCT/US2010/036198
EXAMPLE EC50 EXAMPLE EC50
# #
1 0.712 190 0.55068
2 0.783 191 0.00691
3 0.0142 192 0.00241
4 0.01854 193 0.00076
0.01241 194 0.00819
6 0.03487 195 0.00207
7 0.192 196 0.00172
8 0.158 197 0.0125
9 0.01476 198 0.03619
0.05202 199 0.00506
11 0.01393 200 0.01099
12 0.03471 201 0.59132
13 0.0232 202 0.0438
14 3.8947 203 0.02208
0.01276 204 0.16475
16 1.2098 205 0.01059
17 0.475 206 0.05291
18 0.086 207 0.00376
19 0.465 208 0.12121
0.191 209 0.0045
21 0.062 210 0.06022
22 0.085 211 0.3073
23 0.045 212 0.01283
24 0.00983 213 0.0060976
0.007 214 0.0043751
26 0.05888 215 0.00056038
27 0.33237 216 0.68263
28 0.0419 217 0.0015528
29 0.02047 218 0.0072907
0.01529 219 > 1
- 252 -

CA 02759182 2011-10-18
WO 2010/138588
PCT/US2010/036198
31 0.01565 220 > 1
32 0.08147 221 0.094771
33 0.00711 222 >1
34 0.00748 223 0.18208
35 0.29147 224 0.013887
36 0.18137 225 0.56001
37 0.00118 226 0.1178
38 3.5092 227 0.0073566
39 0.01974 228 > 1
40 0.09974 229 > 1
41 0.05801 230 0.052821
42 0.53412 231 0.52301
43 0.27208 232 > 1
44 0.05309 233 > 1
45 0.00992 234 0.13532
46 > 5 235 0.03232
47 0.03265 236 0.04292
48 0.00333 237 0.05316
49 0.35161 238 0.10303
50 0.31264 239 0.023699
51 0.02308 240 0.017266
52 0.19964 241 0.11377
53 0.06674 242 0.22275
54 1.9158 243 0.80718
55 0.0132 244 0.79378
56 0.08654 245 0.083614
57 0.42611 246 0.40218
58 >5 247 0.092976
59 0.7215 248 0.099588
60 0.05948 250 > 1
61 0.18337 251 0.91782
62 0.02506 252 0.003475
- 253 -

CA 02759182 2011-10-18
WO 2010/138588
PCT/US2010/036198
63 0.00751 253 0.049586
64 0.00025 254 0.019908
65 0.00025 255 0.009004
66 0.01893 256 0.017997
67 0.04954 257 0.026002
68 0.10846 258 0.00055345
69 1.7243 259 0.00038795
70 >5 260 0.0054323
71 0.09165 261 0.18366
72 0.00751 262 0.016346
73 0.02369 263 > 1
74 0.057 264 0.68866
75 0.01509 265 0.0071718
76 0.51131 266 0.0072924
77 0.76196 267 0.06944
78 0.01252 268 0.048792
79 0.0649 269 0.0072346
80 0.06863 270 0.0025216
81 0.04814 271 0.43657
82 0.68383 272 0.84006
83 0.197 273 0.20925
84 0.158 274 0.21418
85 1.95 275 0.14303
86 1.02 276 0.0035006
87 1.18 277 0.0081845
88 0.447 278 0.79393
89 0.06446 279 0.22492
90 0.06299 280 0.45923
91 0.18296 281 0.65371
92 0.08089 282 0.032187
93 >5 283 0.013096
94 1.6946 284 0.16213
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95 0.02954 285 0.057413
96 0.04356 286 0.034464
97 0.05557 287 0.59312
98 0.0229 288 0.39042
99 1.3923 289 0.6687
100 0.13666 290 0.10663
101 0.2991 291 0.016079
102 0.62178 292 0.88938
103 0.03917 293 0.28715
104 0.07125 294 0.12525
105 0.05357 295 0.014803
106 0.82639 296 0.76869
107 0.06117 297 0.59157
108 0.02407 298 0.070305
109 0.18339 299 0.067981
110 0.53638 300 0.76334
111 0.01451 301 >1
112 0.02063 302 0.38106
113 0.00136 303 0.04776
114 0.01078 304 0.29755
115 0.01184 305 0.032539
116 0.02853 306 0.55348
117 0.0182 307 0.12767
118 0.01294 308 0.257
119 0.01138 309 0.052421
120 0.00147 310 > 1
121 0.05972 311 0.035835
122 0.00185 312 0.016178
123 0.00333 313 > 1
124 0.21224 314 0.66006
125 0.00838 315 0.21027
126 0.05359 316 > 1
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127 0.00975 317 0.013313
128 0.00589 318 0.011566
129 0.01484 319 0.0044972
130 0.01059 320 0.050974
131 0.01266 321 0.0188
132 0.02209 322 0.012367
133 0.03186 323 0.71689
134 0.00251 324 0.0045254
135 0.00237 325 0.012319
136 0.00296 326 0.023133
137 0.01272 327 0.0027224
138 0.00152 328 0.0098808
139 0.01681 329 0.42369
140 0.01275 330 0.0097843
141 0.02044 331 0.92638
142 0.34531 332 0.45738
143 0.01914 333 0.46292
144 0.0212 334 > 1
145 0.004 335 0.26951
146 0.01916 336 0.35134
147 0.02618 337 0.001759
148 0.00938 338 0.003399
149 0.01347 339 0.45016
150 0.05103 340 0.05646
151 0.03372 341 0.031652
152 0.02037 342 0.050891
153 0.01723 343 0.12664
154 0.02647 344 0.0066616
155 0.59421 345 0.0092536
156 0.00805 346 0.19003
157 0.01086 347 0.018849
158 0.01793 348 0.050263
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159 0.01179 349 0.023086
160 0.08363 350 0.0058378
161 0.03465 351 0.0020618
162 0.01297 352 0.0011961
163 0.00432 353 0.0050512
164 0.01476 354 0.053231
165 0.0051 355 0.018771
166 0.01185 356 0.026623
167 0.00093 357 0.013235
168 0.08867 358 0.0038131
169 0.07626 359 0.0059243
170 0.12515 360 0.0098968
171 0.05272 361 0.00053755
172 0.02053 362 0.031726
173 0.00516 363 0.02643
174 0.12621 364 0.011244
175 > 1 365 0.0030168
176 0.13353 366 0.016548
177 0.15936 367 nd
178 0.20234 368 nd
179 0.04273 369 0.0079974
180 0.0118 370 nd
181 0.10612 371 0.007165
182 0.1234 372 nd
183 0.01753 373 nd
184 0.02323 374 0.015475
185 0.02747 375 0.56013
186 0.06443 376 0.008765
187 0.21494 377 0.002377
188 0.01638 378 0.006764
189 0.14397
nd = not determined
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CA 02759182 2015-04-17
TABLE 3 shows the utility of compounds having Formula I to functionally
inhibit
anti-apoptotic Bc1-2 protein in a cellular context. The acute lymphoblastic
leukemia (ALL)
cell line RS4;I.1 has been shown by BI13 profiling, a mitochondrial assay that
classifies
blocks in the intrinsic apoptotic pathway, to be highly dependant on Bc1-2 for
survival and is
sensitive to the Bc1-2 family member inhibitor ABT-737 (Blood, 2008, Vol. 111,
2300-2309).
The ability of compounds to kill RS4;11 cells is a direct measure of the
compounds ability to
inhibit anti-apoptotic Bel-2 protein function. Compounds of Formula I are very
effective in
killing RS4;11 cells as demonstrated by low EC50 values.
Compounds taught in US Publication No. US 2010-0152183, entitled "BCL-2-
SELECTIVE APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER
AND IMMUNE DISEASES," filed on December 4, 2009, have utility for the
treatment of
various cancers and auto-immune diseases due to their activity against Bc1-2
family proteins,
and more specifically Bc1-2. These compounds bind to Bc1-2 with high affinity
in a FRET
based assay described in US 2010-0152183. The administration of a one or more
of these compounds
to cells that are dependant on Bc1-2 or Bc1-2 family proteins for survival,
such as the RS4:11
B-cell leukemia human tumor cell line, results in apoptosis, also known as
programmed cell
death. The amount of apoptosis caused by administration of the compound is
represented by
the EC50 in the cell viability assay, which is a measure of the number of
living cells after
administration of compound.
TABLE 4 identifies certain compounds (described below in Examples in 19, 20,
23
and 92 and described more fully in US 2010-0152183,
with the various substituents being defined by R, X and Y as set forth. As can

be seen from TABLE 4, these compounds exhibit a trend of increasing binding
affinity (IQ
for Bel-2 with increasing levels of apoptosis, or cell death, in the Bc1-2
dependant tumor cell
line RS4;11. On this basis, the inventors expect that compounds with even
greater affinity
towards Bc1-2 than those compounds shown in Table 4 will exhibit a similar
trend,
potentially eliciting even greater levels of apoptosis, when administered to
cells dependent on
Bc1-2 for survival.
Table 4. Selected compounds in US Publication No. US 2010-0152183,
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NO2
0 R
H
0 N'S
02
(--x-
: 101
N--
H
N
C )
N
I Y
lei
CI
Bc1-2 FRET RS4;11 EC50
EXAMPLE R X Y
Ki ( ,M) (PM)
1-1,0
(23) .\,N c 0 0.000083 0.045
,c)
(92) C c C 0.000128 0.081
H
(20) µ,... N.,...,...--...,0,- c
C 0.000181 0.191
H
(19) NI- C C 0.000226 0.465
,c)
To this end, binding affinity and cellular activity for compounds according to
the
present invention were compared with structurally similar indole compounds. In
particular,
the compounds of the present invention, in which a nitrogen is contained at a
specific position
within the heteroarene fused to the heteroaryl ring were compared with the
corresponding
indole compounds, which latter compounds lack only the specific nitrogen
substitution
included in the compounds of the present invention.
As can be seen in TABLE 5, compounds of the present invention having the
specific
nitrogen substitutions shown (i.e., compounds of Examples 1, 2, 3, 4, 5, 6, 9,
10, 11, 12, 13,
15, 16, and 17, where Z = N) in fact achieve relatively greater levels of
apoptosis when
administered to cells that depend on Bc1-2 for survival and have increased
affinity towards
Bc1-2 relative to the corresponding structural analogs lacking the specific
nitrogen
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=:.CA 02759182 2015-06-16
=
substitution (i.e., compounds of Examples 87, 88, 89, 90, 91, 19, 20, 21, 92,
22, 23, 93, and
94, respectively, where Z = C, taught in U.S. Patent Application No.
61/181,180).
Specifically, the seventh column of TABLE 5 compares binding affinity of
compounds of the present invention (the compound identified by the designated
substituents
in the uppermost row in each pair of rows set apart by blank rows) to
corresponding
compounds lacking the described nitrogen substitution. In each comparison,
compounds of
the present application (upper row of each pair of rows separated by a blank
row) bind Bc1-2
with greater affinity to Bc1-2 than the corresponding analogs (lower row of
each pair of rows
separated by a blank row).
Further, column 8 of TABLE 5 compares the amount of apoptosis in the Bc1-2
dependant RS4;11 cell line achieved using compounds of the present invention
(again the
compound identified by the designated substituents in the uppermost row in
each pair of rows
set apart by blank rows) to that achieved using compounds of Examples 87, 88,
89, 90, 91,
19, 20, 21, 92, 22, 23, 93, and 94, where Z = C. In each comparison, compounds
of the
present invention (upper row of each pair of rows separated by a blank row)
achieve greater
extent of apoptosis in Bc1-2 dependent RS4;11 cells than the corresponding
analogs (lower
row of each pair of rows separated by a blank row).
The increase in binding affinity between the compounds of the present
invention and
corresponding analogs ranges from 2.7x to greater than 100x, and the increased
potency in
RS4;11 cells ranges from a 1.65x increase to greater than 10x increase.
As detailed below, a specific substitution of a nitrogen atom for a carbon
atom leads
to unexpected increase in binding affinity to antiapoptotic Bc1-2 and increase
in potency in
cell viability assays assessing apoptosis in Bc1-2 dependent cell lines.
This invention therefore comprises a series of compounds that demonstrate
unexpected properties with respect to their binding to and inhibiting the
activity of anti-
apoptotic Bc1-2 protein to a significantly greater extent than corresponding
analog
compounds.
TABLE 5. Direct comparison of compounds of the present invention with
corresponding
analogs.
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X Fil
1
H .1 W
0 N'S
o 02
e el
N---z
H
N
C )
N
1 ring
1.1
CI
Bc1-2 FRET
RS4;11
EXAMPLE R W X Ring Z
ki ( M)
EC50 ( M)
.'0 se
(1) k'') NH NO2 s IW
,:. N 0.000225 0.712
0 1 i
, IW
(87) k'') NH NO2 -,,,. C 0.000618 1.180
1
(2) ' i ' ' NO0 NH NO2 i
, IW
-,,,. N < 0.000010 0.783
'2(-N I i
, IW
(88) 0 NH NO2 1 C 0.672 0.447
Co /
(3)
NH NO2 IW N 0.000013 0.0142
Co /
(89)
õ(01 NH NO2 IW C 0.000074 0.064
(4) NH NO2 / N <0.00001 0.019
`',Lal IW
N.
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0\1
(90) NH NO2 / __ O
C 0.000013 0.063
\
o
/
(5) /') NH NO2 * _____________
N <
0.00001 0.012
o
/
(18) /') NH
NO2 .,,,. IW C
0.000017 0.086
(6) rf NH NO2 / _____________________________ *
N
0.000018 0.035
(91) rr NH
r\l,. NO2 N./ * C
0.000487 0.183
r'o /
(9) r'' NH NO2 .,,,. IW N <
0.00001 0.015
\'=
r'o /
(19) ('. NH NO2 h1/4 IW C
0.000226 0.465
/
(10) NH NO2 * _____________________________
N <
0.00001 0.052
/
(20) NH NO2 _______ O
C 0.000181 0.191
0 / _________________________________
s(x;
(11) NH NO2 .,,,. IW N
0.000016 0.014
(21) NH NO2 / __ *
C 0.000912 0.062
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CA 02759182 2011-10-18
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(12)rci)
0 NO2 'ô
N < 0.00001 0.035
l'o)
(92) rci)
0 NO2 / &
N. C 0.000128 0.081
c))
(13) NH NO2 &N. N < 0.00001 0.023
(22)
NH NO2 / _________________________________ *
C 0.000291 0.085
(:) / &
(15) /') NH NO2 N. N < 0.00001 0.013
/
(23) NH NO2 / *C 0.000083 ____ 0.045
/
(16) NH SO2CF3 N.,. W N 0.000219 1.210
/
(93) NH SO2CF3 IW C 0.035 >
5.000
/
W
(17) NH SO2CF3 / & N 0.000090 0.475
(:) /
(94) /') NH SO2CF3 IW C 0.000678 1.690
More specifically, compounds of the present invention contain a substitution
pattern
shown in the diagram below.
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CA 02759182 2011-10-18
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0 \
0
* I \
N
H
¨
Other compounds that contain isomeric ring systems to that shown above, such
as
those rings systems containing a nitrogen adjacent to the oxygenated carbon
within the ring,
as shown below, are compromised by instability.
x
14,1Iv'R
02S
0 NH
T 1
101 Q Q ..." = I \
N
N Or I I\...õ. \
- N
H
N H
( ) 5-substituted-1H-pyrro1o[2,3-
c]pyridine 5-substituted-1H-
N pyrrolo[3,2-
b]pyridine
l Y
[10
ci
Specifically, this was discovered by the inventors in the following compound
preparation. The intermediate structure F, that directly precedes the final
product of the
unstable compound, was prepared according to the route below. All
intermediates A-F were
stable and isolable using techniques known to those skilled in the art.
1
0 0 0 0 ¨0/ ¨0¨\_ / 4
2M 1 N COe
\ CI\I-
OH F....V-a'= . NaH 40 0 1 ....
N.,,..
ISI N /
_________________________________ 0 'NO2 NNO2 ___ ).-
NI ,LNO2
F F A F B
I
o o
o..,..-
0
H Na*
Lp,o.õ.e 0 ....õ..,..,
N I
CO2Me C ) 0 0
H
{H21 0 ,
___________ 0 CCIN' ___ N
H 0 C
- 10 '8 N
.- ' C )
N N
H H
F N
C C ) D le E
N
H
CI
0 OH
0
110 CC
base H
C )
N
40 1.
10 Cl F
Intermediate F, shown in the scheme above, was reacted with intermediate G
using
standard coupling conditions that are known to those skilled in the art. The
reaction mixture
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CA 02759182 2011-10-18
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was analyzed via HPLC/MS to monitor the formation of a peak corresponding to
the
compound H. While this peak formed within hours of initiating the reaction
below, the peak
progressively disappeared during workup and chromatography, until it no longer
was present.
The lack of stability of the putative compound originates from the position of
the nitrogen
within the fused ring-system described above. This position, which is adjacent
to the oxygen-
bearing carbon in the 5-substituted-1H-pyrrolol2,3-clpyridine ring system
shown below and
described above, makes the compound H unstable.
'N'
CO21-I 03 40
Ail 0
1
0 NH
41111r HCI NO2 O 02 H0
o ad N
0 is
, 40 't\Cc
N
=

X
NH2
I
CI le
1101
CI
It is expected that a compound containing the fused 5-substituted-1H-
pyrrolol3,2-
blpyridine ring system below would be similarly unstable, since the position
of the nitrogen
is adjacent to the oxygen-bearing carbon within the ring.
O
0 N
I
N
Therefore, compounds with the 5-substituted-1H-pyrrolol2,3-blpyridines are
preferred over the isomeric compounds.
It is expected that, because compounds having Formula (I) bind to Bc1-2, they
would
also have utility as binders to anti-apoptotic proteins having close
structural homology to Bel-
2, such as, for example, anti-apoptotic Bc1-XL, Bcl-w, Mc1-1 and Bfl-1/A1
proteins.
Involvement of Bc1-2 proteins in bladder cancer, brain cancer, breast cancer,
bone
marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,
lymphoid
malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral
cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small
cell lung cancer,
chronic lymphocytic leukemia, myeloma, prostate cancer spleen cancer, and the
like is
described in commonly-owned PCT US 2004/36770, published as WO 2005/049593,
and
PCT US 2004/37911, published as WO 2005/024636.
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CA 02759182 2015-04-17
Involvement of Bc1-2 proteins in immune and autoimmune diseases is described
in
Current Allergy and Asthma Reports 2003, 3, 378-384; British Journal of
Haematology 2000,
110(3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of
Medicine 2004,
351(14), 1409-1418.
Involvement of Bc1-2 proteins in arthritis is disclosed in commonly-owned
United
States Provisional Patent Application Serial No. 60/988,479.
Involvement of Bc1-2 proteins in bone marrow transplant rejection is disclosed
in
commonly-owned United States Publication No. 2008-0182845.
Overexpression of Bc1-2 proteins correlates with resistance to chemotherapy,
clinical
outcome, disease progression, overall prognosis or a combination thereof in
various cancers
and disorders of the immune system. Cancers include, but are not limited to,
hematologic
and solid tumor types such as acoustic neuroma, acute leukemia, acute
lymphoblastic
leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma,

angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast
cancer (including
estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's
lymphoma,
cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic
lymphocytic leukemia, chronic niyelocytic (granulocytic) leukemia, chronic
myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma,
dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma,
endometrial
cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,
esophageal
cancer, estrogen-receptor positive breast cancer, essential thrombocythemia,
Ewing's tumor,
fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational
trophobalstic disease,
glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma,
hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma,
liposarcoma,
lung cancer (including small cell lung cancer and non-small cell lung cancer),

lymphangioendothelio-sarcoma, lymphangiosarcoma, lyrnphoblastic leukemia,
lymphoma
(lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma,
Hodgkin's
lymphoma and non-Hodgkin's lymphoma), malignancies and hyperproliferative
disorders of
the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and
uterus, lymphoid
malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,
medulloblastoma,
melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic
sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas,
papillary carcinoma,
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peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer
(including
hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell
carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma,
seminoma, skin
cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas),
stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer
(including
germ cell testicular cancer), thyroid cancer, Waldenstrom's macroglobulinemia,
testicular
tumors, uterine cancer, Wilms' tumor and the like.
It is also expected that compounds having Formula (I) would inhibit growth of
cells
expressing Bc1-2 proteins derived from a pediatric cancer or neoplasm
including embryonal
rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute
myelogenous
leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic
ependymoma, pediatric
anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,
pediatric atypical
teratoid/rhabdoid tumor of the central nervous system, pediatric biphenotypic
acute leukemia,
pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors
such as primitive
neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric
favorable
histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma,
pediatric
neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-
B-cell
cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney
tumor,
pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and
skin cancer
and the like.
Autoimmune disorders include acquired immunodeficiency disease syndrome
(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,
inflammatory
diseases, and thrombocytopenia, acute or chronic immune disease associated
with organ
transplantation, Addison's disease, allergic diseases, alopecia, alopecia
areata, atheromatous
disease/arteriosclerosis, atherosclerosis, arthritis (including
osteoarthritis, juvenile chronic
arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive
arthritis), autoimmune
bullous disease, abetalipoprotemia, acquired immunodeficiency-related
diseases, acute
immune disease associated with organ transplantation, acquired acrocyanosis,
acute and
chronic parasitic or infectious processes, acute pancreatitis, acute renal
failure, acute
rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic
beats, adult
(acute) respiratory distress syndrome, AIDS dementia complex, alcoholic
cirrhosis, alcohol-
induced liver injury, alcohol-induced hepatitis, allergic conjunctivitis,
allergic contact
dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-
1- antitrypsin
deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina
pectoris,
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ankylosing spondylitis associated lung disease, anterior horn cell
degeneration, antibody
mediated cytotoxicity, antiphospholipid syndrome, anti-receptor
hypersensitivity reactions,
aortic and peripheral aneurysms, aortic dissection, arterial hypertension,
arteriosclerosis,
arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy,
atrial fibrillation
(sustained or paroxysmal), atrial flutter, atrioventricular block, atrophic
autoimmune
hypothyroidism, autoimmune haemolytic anaemia, autoimmune hepatitis, type-1
autoimmune
hepatitis (classical autoimmune or lupoid hepatitis), autoimmune mediated
hypoglycaemia,
autoimmune neutropaenia, autoimmune thrombocytopaenia, autoimmune thyroid
disease, B
cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,
bronchiolitis
obliterans, bundle branch block, bums, cachexia, cardiac arrhythmias, cardiac
stun syndrome,
cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response,
cartilage
transplant rejection, cerebellar cortical degenerations, cerebellar disorders,
chaotic or
multifocal atrial tachycardia, chemotherapy associated disorders, chlamydia,
choleosatatis,
chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome,
chronic immune
disease associated with organ transplantation, chronic eosinophilic pneumonia,
chronic
inflammatory pathologies, chronic mucocutaneous candidiasis, chronic
obstructive
pulmonary disease (COPD), chronic salicylate intoxication, colorectal common
varied
immunodeficiency (common variable hypogammaglobulinaemia), conjunctivitis,
connective
tissue disease associated interstitial lung disease, contact dermatitis,
Coombs positive
haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease, cryptogenic
autoimmune
hepatitis, cryptogenic fibrosing alveolitis, culture negative sepsis, cystic
fibrosis, cytokine
therapy associated disorders, Crohn's disease, dementia pugilistica,
demyelinating diseases,
dengue hemorrhagic fever, dermatitis, dermatitis scleroderma, dermatologic
conditions,
dermatomyositis/polymyositis associated lung disease, diabetes, diabetic
arteriosclerotic
disease, diabetes mellitus, Diffuse Lewy body disease, dilated cardiomyopathy,
dilated
congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal
ganglia,
disseminated intravascular coagulation, Down's Syndrome in middle age, drug-
induced
interstitial lung disease, drug-induced hepatitis, drug-induced movement
disorders induced by
drugs which block CNS dopamine, receptors, drug sensitivity, eczema,
encephalomyelitis,
endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, Epstein-
Barr virus infection,
erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic
lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia,
functional peripheral
arterial disorders, female infertility, fibrosis, fibrotic lung disease,
fungal sepsis, gas
gangrene, gastric ulcer, giant cell arteritis, glomerular nephritis,
glomerulonephritides,
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Goodpasture's syndrome, goitrous autoimmune hypothyroidism (Hashimoto's
disease), gouty
arthritis, graft rejection of any organ or tissue, graft versus host disease,
gram negative sepsis,
gram positive sepsis, granulomas due to intracellular organisms, group B
streptococci (GBS)
infection, Grave's disease, haemosiderosis associated lung disease, hairy cell
leukemia, hairy
cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever,
heart transplant
rejection, hemachromatosis, hematopoietic malignancies (leukemia and
lymphoma),
hemolytic anemia, hemolytic uremic syndrome/thrombolytic thrombocytopenic
purpura,
hemorrhage, Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C,
HIV
infection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's
chorea,
hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity
pneumonitis,
hyperthyroidism, hypokinetic movement disorders, hypothalamic-pituitary-
adrenal axis
evaluation, idiopathic Addison's disease, idiopathic leucopaenia, idiopathic
pulmonary
fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver disease, infantile
spinal muscular
atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel
disease, insulin
dependent diabetes mellitus, interstitial pneumonitis,
iridocyclitis/uveitis/optic neuritis,
ischemia-reperfusion injury, ischemic stroke, juvenile pernicious anaemia,
juvenile
rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma,
Kawasaki's disease,
kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of
the corticospinal
system, linear IgA disease, lipidema, liver transplant rejection, Lyme
disease, lymphederma,
lymphocytic infiltrative lung disease, malaria, male infertility idiopathic or
NOS, malignant
histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic
vasculitis of
the kidneys, migraine headache, mitochondrial multisystem disorder, mixed
connective tissue
disease, mixed connective tissue disease associated lung disease, monoclonal
gammopathy,
multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shi-
Drager and
Machado-Joseph), myalgic encephalitis/Royal Free Disease, myasthenia gravis,
microscopic
vasculitis of the kidneys, mycobacterium avium intracellulare, mycobacterium
tuberculosis,
myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders,

nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis,
nephrotic
syndrome, neurodegenerative diseases, neurogenic I muscular atrophies,
neutropenic fever,
Non-alcoholic Steatohepatitis, occlusion of the abdominal aorta and its
branches, occlusive
arterial disorders, organ transplant rejection, orchitis/epidydimitis,
orchitis/vasectomy
reversal procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian
failure, pancreas
transplant rejection, parasitic diseases, parathyroid transplant rejection,
Parkinson's disease,
pelvic inflammatory disease, pemphigus vulgaris, pemphigus foliaceus,
pemphigoid,
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perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease,
peripheral vascular
disorders, peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis
carinii
pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy,
monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome,
post pump
syndrome, post-MI cardiotomy syndrome, postinfectious interstitial lung
disease, premature
ovarian failure, primary biliary cirrhosis, primary sclerosing hepatitis,
primary myxoedema,
primary pulmonary hypertension, primary sclerosing cholangitis, primary
vasculitis,
Progressive supranucleo Palsy, psoriasis, psoriasis type 1, psoriasis type 2,
psoriatic
arthropathy, pulmonary hypertension secondary to connective tissue disease,
pulmonary
manifestation of polyarteritis nodosa, post-inflammatory interstitial lung
disease, radiation
fibrosis, radiation therapy, Raynaud's phenomenon and disease, Raynoud's
disease, Refsum's
disease, regular narrow QRS tachycardia, Reiter's disease, renal disease NOS,
renovascular
hypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoid
arthritis associated
interstitial lung disease, rheumatoid spondylitis, sarcoidosis, Schmidt's
syndrome,
scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsis
syndrome, septic
shock, seronegative arthropathies, shock, sickle cell anemia, Sjogren's
disease associated lung
disease, Sjorgren's syndrome, skin allograft rejection, skin changes syndrome,
small bowel
transplant rejection, sperm autoimmunity, multiple sclerosis (all subtypes),
spinal ataxia,
spinocerebellar degenerations, spondyloarthropathy, spondyloarthopathy,
sporadic,
polyglandular deficiency type I sporadic, polyglandular deficiency type II,
Still's disease,
streptococcal myositis, stroke, structural lesions of the cerebellum, Subacute
sclerosing
panencephalitis, sympathetic ophthalmia, Syncope, syphilis of the
cardiovascular system,
systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset
juvenile
rheumatoid arthritis, systemic lupus erythematosus, systemic lupus
erythematosus-associated
lung disease, systemic sclerosis, systemic sclerosis-associated interstitial
lung disease, T-cell
or FAB ALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Thl
Type mediated
diseases, thromboangitis obliterans, thrombocytopenia, thyroiditis, toxicity,
toxic shock
syndrome, transplants, trauma/hemorrhage, type-2 autoimmune hepatitis (anti-
LKM antibody
hepatitis), type B insulin resistance with acanthosis nigricans, type III
hypersensitivity
reactions, type IV hypersensitivity, ulcerative colitic arthropathy,
ulcerative colitis, unstable
angina, uremia, urosepsis, urticaria, uveitis, valvular heart diseases,
varicose veins, vasculitis,
vasculitic diffuse lung disease, venous diseases, venous thrombosis,
ventricular fibrillation,
vitiligo acute liver disease, viral and fungal infections, vital
encephalitis/aseptic meningitis,
vital-associated hemaphagocytic syndrome, Wegener's granulomatosis, Wernicke-
Korsakoff
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syndrome, Wilson's disease, xenograft rejection of any organ or tissue,
yersinia and
salmonella-associated arthropathy and the like.
Schemes and Experimentals
The following abbreviations have the meanings indicated. ADDP means
1,1'-(azodicarbonyl)dipiperidine; AD-mix-13 means a mixture of (DHQD)2PHAL,
K3Fe(CN)6,
K2CO3, and K2S 04; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means
tert-butoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1,4-phthalazinediy1
diethyl
ether; DBU means 1,8-diazabicyclol5.4.01undec-7-ene; DIB AL means
diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means N,N-
dimethylaminopyridine;
DMF means N,N-dimethylformamide; dmpe means 1,2-bis(dimethylphosphino)ethane;
DMSO means dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)-butane;
dppe
means 1,2-bis(diphenylphosphino)ethane; dppf means 1,1'-
bis(diphenylphosphino)ferrocene;
dppm means 1,1-bis(diphenylphosphino)methane; EDAC=HC1 means 1-(3-
dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride; Fmoc means
fluorenylmethoxycarbonyl; HATU means 0-(7-azabenzotriazol-1-y1)-N,N'N'N'-
tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide;
IPA
means isopropyl alcohol; MP-BH3 means macroporous triethylammonium
methylpolystyrene
cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF
means
tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine;
NMP
means N-methylpyrrolidine; PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most
useful
and readily understood description of procedures and conceptual aspects of
this invention.
Compounds of this invention may be made by synthetic chemical processes,
examples of
which are shown herein. It is meant to be understood that the order of the
steps in the
processes may be varied, that reagents, solvents and reaction conditions may
be substituted
for those specifically mentioned, and that vulnerable moieties may be
protected and
deprotected, as necessary.
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SCHEME 1
CO2R CO2R CO2R CO2H
401 ____________________ 0 ________________ 0 _______________ 0
_ .
N
y (1)0 X õ (2) (3) (4)
HO" IT 1
1.0 1 0-11
'Z3 R57 L`z3 R57 LY
Compounds of Formula (4) can be prepared as shown in SCHEME 1, and can be used

as described in SCHEME 8 to prepare compounds of Formula (I), which are
representative of
the compounds of the present invention. Compounds of Formula (1) wherein R is
alkyl, can
be converted to compounds of Formula (2) using Z3L1MgX1, wherein X1 is a
halide, in a
solvent such as but not limited to ether or tetrahydrofuran. Compounds of
Formula (3) can be
prepared from compounds of Formula (2) using a strong base such as NaH and
R57X2,
wherein X2 is a halide and R57 is as described herein. Compounds of Formula
(3), when
treated with aqueous NaOH or Li0H, will provide compounds of Formula (4).
SCHEME 2
R37A CO2R CO2H
CO2R
0 Z3
lei(6) lei
el _______________________
..- .-
N N
CN C ) C )
) N N
N =L
H (5) R37A Z3 (7) R37A Z3 (8)
As shown in SCHEME 2, compounds of Formula (5) can be reacted with compounds
of Formula (6) and a reducing agent to provide compounds of Formula (7).
Examples of
reducing agents include sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, polymer supported cyanoborohydride, and the like. The
reaction is
typically performed in a solvent such as but not limited to methanol,
tetrahydrofuran, and
dichloromethane or mixtures thereof. Compounds of Formula (8) can be prepared
from
compounds of Formula (7) as described in SCHEME 1, and can be used as
described in
SCHEME 8 to prepare compounds of Formula (I).
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SCHEME 3
Br
CO2R J CO2R CO2R co2H
el V
X (10) el Y-B(OH)2 0
___________________________________________________________ i.- el
CN N N rN
) C ) (11) L CN) (13) N) (14)
N N
z3 z3 z3
X I
Y 1
Y
Compounds of Formula (9), when reacted with a compound a Formula (10) wherein
X is a halide or triflate, and a base will provide a compound of Formula (11).
Bases useful in
the reaction include triethylamine, diisopropylethylamine and the like.
Compounds of
Formula (13), wherein Y is as described herein for substituents on Z3, can be
prepared from
compounds of Formula (11) and compounds of Formula (12) using Suzuki coupling
conditions known to those skilled in the art and readily available in the
literature. Compounds
of Formula (14) can be prepared from compounds of Formula (13) as described in
SCHEME
1, and can be used as described in SCHEME 8 to prepare compounds of Formula
(I).
SCHEME 4
R38B(OH)2 CO2R,.-OH
O$ì_00 (16) CO2R R3,-,5 R38 . R3(.-5
FCFiip ________________________________________________________________ -C)
, _
F ..-
--)
(15) (17) (18)
(19)
CO2R CO2H
(5)
0 ________________ 10
______________ . ..-
CN ) CN )
N N
b b
R38 R38
(20) (21)
As shown in SCHEME 4, compounds of Formula (17) can be prepared from
compounds of Formula (15) and compounds of Formula (16), wherein R is alkyl
and R38 is as
described herein, using Suzuki coupling conditions known to those skilled in
the art and
readily available in the literature. Compounds of Formula (17) can be reduced
to compounds
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of Formula (18) using a reducing agent such as LiA1H4 in a solvent such as but
not limited to
diethyl ether or THF. Compounds of Formula (19) can be prepared from compounds
of
Formula (18) using Dess-Martin periodinane or Swem oxidation conditions known
to those
skilled in the art and readily available in the literature. Compounds of
Formula (19) can be
reacted with a compound of Formula (5) and a reducing agent to provide
compounds of
Formula (20). Examples of reducing agents include sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride, polymer supported
cyanoborohydride, and
the like. The reaction is typically performed in a solvent such as but not
limited to methanol,
tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixtures thereof.
Compounds of
Formula (21) can be prepared from compounds of Formula (20) as described in
SCHEME 1,
and can be used as described in SCHEME 8 to prepare compounds of Formula (I).
SCHEME 5
CO2R CO2R
0
X1
Z2., 1 z2.L1
Y (22) (23)
Z3 Z3
As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, may be
converted to compounds of Formula (23) by reacting the former, wherein X1 is
Cl, Br, I, or
CF3503-, and compounds of Formula R41-0H and a catalyst, with or without a
first base.
Examples of catalysts include copper(I) trifluoromethanesulfonate toluene
complex, PdC12,
Pd(OAc)2, and Pd2(dba)3. Examples of first bases include triethylamine, N,N-
diisopropylethylamine, Cs2CO3, Na2CO3, K3PO4, and mixtures thereof.
Compounds of Formula (22) may also be converted to compounds of Formula (23)
by
reacting the former, when X1 is Cl, F, or NO2, and compounds of Formula R41-0H
with a
first base. Examples of first bases include triethylamine, N,N-
diisopropylethylamine,
Cs2CO3, Na2CO3, K3PO4, and mixtures thereof.
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SCHEME 6
CO2 R
\./
is o,R41
0y0
H (26)
OH N
(N ) F
___________________________________________________________________ -
(1 8)
R38 . (24) R38
(25)
CO2 R CO2H
, A 1
0 0 R,. 0 o,R41
N N
N N
b
R (27) R b (28)
38 38
Compounds of Formula (18) can be reacted with mesyl chloride and a base such
as
but not limited to triethylamine, followed by N-t-butoxycarbonylpiperazine, to
provide
compounds of Formula (24). Compounds of Formula (25) can be prepared by
reacting
compounds of Formula (24) with triethylsilane and trifluoroacetic acid.
Compounds of
Formula (25) can be reacted with compounds of Formula (26) and HK2PO4 to
provide
compounds of Formula (27) in a solvent such as but not limited to
dimethylsulfoxide.
Compounds of Formula (28) can be prepared from compounds of Formula (27) as
described
in SCHEME 1, and can be used as described in SCHEME 8 to prepare compounds of
Formula (I).
SCHEME 7
O CO2R CO2H
CO2 R 410 P+(29)
1.3-;
0 *
el * /
- _________________________ / R 5 7 NN
N ______________________ ..-
...-- ...
Y 1
D' I
0 (1) (30) (31 )
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As shown in SCHEME 7, compounds of Formula (1) can be reacted with an
appropriate triphenylphosphonium bromide of Formula (29) and a base such as
but not
limited to sodium hydride or n-butyllithium to provide compounds of Formula
(30). The
reaction is typically performed in a solvent such as THF or DMSO. Compounds of
Formula
(31) can be prepared from compounds of Formula (30) as described in SCHEME 1,
and can
be used as described in SCHEME 8 to prepare compounds of Formula (I).
SCHEME 8
l (4), (8), (14), Z2A
i0\õ/0 El 0 0 E
_______________________________ H2N
slYl ,syl (31),, or (38)
1 .-*--,
D1

IA1131 D1/A1B1 1 H
Z1A Di A1131
(32) (33) (I)
As shown in SCHEME 8, compounds of Formula (32), which can be prepared as
described herein, may be converted to compounds of Formula (33) by reacting
the former
with ammonia. Compounds of Formula (33) may be converted to compounds of
Formula (I)
by reacting the former and compounds of Formula (4), (8), (14), (21), (28),
(31), or (38) and a
coupling agent, with or without a first base. Examples of coupling agents
include 1-ethy1-3-
1L3-(dimethylamino)propyll-carbodiimide hydrochloride, 1,1'-
carbonyldiimidazole, and
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate. Examples
of first
bases include triethylamine, N,N-diisopropylethylamine, 4-
(dimethylamino)pyridine, and
mixtures thereof.
SCHEME 9
z2A
I V
Z3. ---Z2.
Li Zi Cl
R/0 El 0µ 10 El
1 (34) z2A
,\SIY1 -SY1 z 1
CI 1
_______________________________ H2N lA I
l
D1A1- B1 D1' Al B1 1 1-1ZIA '-'
÷
Al Bi
ni
(32) (33) (I)
Compounds of Formula (33), prepared as described in SCHEME 8, may also be
converted to compounds of Formula (I) by reacting the former and compounds of
Formula
(34) and a first base. Examples of first bases include but are not limited to
sodium hydride,
triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and
mixtures thereof.
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SCHEME 10
() 0 OR 0 OH
N
CO2R (36)
Ll,z3 .R41 .R41
.R41
() C
(35) N 11
z3 L,1
z3
(37) (38)
As shown in SCHEME 10, compounds of Formula (35), wherein L is a bond, alkyl,
0, S, S(0), S(0)2, NH, etc., can be reacted with compounds of Formula (36), to
provide
compounds of Formula (37). The reaction is typically performed at elevated
temperatures in a
solvent such as but not limited to dimethylsulfoxide, and may require the use
of a base such
as but not limited to potassium phosphate, potassium carbonate, and the like.
Compounds of
Formula (38) can be prepared from compounds of Formula (37) as described in
SCHEME 1,
and can be used as described in SCHEME 8 to prepare compounds of Formula (I).
SCHEME 11
0y0
0 OH 0 OH
H is H C C
N OH N 0-R57
X
(39A) (39)
(40) (41)
Compounds of Formula (39), wherein Y is as described herein for substituents
on Z3,
can be prepared from compounds of Formula (39A) wherein X is a halide or
triflate, and Y-
B(OH)2 using Suzuki coupling conditions known to those skilled in the art and
readily
available in the literature. Compounds of Formula (39) can be reacted with
tert-butyl
piperazine-l-carboxylate and a reducing agent such as sodium
triacetoxyborohydride to
provide compounds of Formula (40). The reaction is typically performed in a
solvent such as
but not limited to methylene chloride. Compounds of Formula (41) can be
prepared from
compounds of Formula (40) by reacting the latter with R57X, wherein X is a
halide, and NaH
in a solvent such as N,N-dimethylformamide, and then the resulting material
can be treated
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with triethylsilane and trifluoroacetic acid in dichloromethane. Compounds of
Formula (41)
can be used as described in Scheme 10 wherein L1-Z3 is as shown in Formula
(41).
SCHEME 12
R37A
0
Z3 H H
H r N 0 N
r N (6) r
1,..N R-' ' -)..- C N ....... R57
00". 57
L-L
N R R37A Z3 R37A Z3
(42) (43)
As shown in SCHEME 12, substituted piperazin-2-ones wherein R57 is alkyl, can
be
reacted with compounds of Formula (6) and a reducing agent such as sodium
triacetoxyborohydride in dichloromethane to provide compounds of Formula (42).

Compounds of Formula (42) can be reduced to compounds of Formula (43) using a
reducing
agent such as but not limited to lithium aluminum hydride in a solvent such as
but not limited
to tetrahydrofuran. Compounds of Formula (43) can be used as described in
Scheme 10
wherein L1-Z3 is as shown in Formula (43).
The following examples are presented to provide what is believed to be the
most
useful and readily understood description of procedures and conceptual aspects
of this
invention. The exemplified compounds were named using ACD/ChemSketch Version
5.06
(05 June 2001, Advanced Chemistry Development Inc., Toronto, Ontario),
ACD/ChemSketch Version 12.01 (13 May 2009), Advanced Chemistry Development
Inc.,
Toronto, Ontario), or ChemDraw Ver. 9Ø5 (CambridgeSoft, Cambridge, MA).
Intermediates were named using ChemDraw Ver. 9Ø5 (CambridgeSoft, Cambridge,
MA).
EXAMPLE 1
4-14- 1(4'-chloro-1,1'-bipheny1-2-y0methyllpiperazin-1-yll-N-(13-nitro-4-
Rtetrahydro-2H-
pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 1A
tert-butyl 44(4'-chlorobipheny1-2-y0methyl)piperazine-1-carboxylate
4'-Chlorobipheny1-2-carboxaldehyde (4.1 g), tert-butyl piperazine-l-
carboxylate (4.23
g), and sodium triacetoxyborohydride (5.61 g) in CH2C12 (60 mL) were stirred
for 24 hours.
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The reaction was quenched with methanol and poured into ether. The solution
was washed
with water and brine, concentrated, and chromatographed on silica gel with 2-
25% ethyl
acetate/hexanes.
EXAMPLE 1B
14(4'-chlorobipheny1-2-yl)methyl)piperazine
EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred in CH2C12 (30 mL)
and
trifluoroacetic acid (30 mL) for 2 hours, and the reaction was concentrated,
and then taken up
in ether and concentrated again. The material was taken up in dichloromethane
(200 mL) and
NaHCO3 solution (100 mL), and partitioned. The organic layer was dried over
Na2SO4, and
condensed to give the title compound.
EXAMPLE 1C
tert-butyl 4-(44(4'-chlorobipheny1-2-yl)methyl)piperazin-1-y1)-2-
fluorobenzoate
Tert-butyl 4-bromo-2-fluorobenzoate (14.0 g), EXAMPLE 1B (16.05 g), Pd2(dba)3
(tris(dibenzylideneacetone)dipalladium(0))(1.40 g), 2-(di-tert-
butylphosphino)biphenyl (1.82
g), and K3PO4 (16.2 g) were stirred in 1,2-dimethoxyethane (300 mL) at 80 C
for 24 hours.
The reaction was cooled and concentrated. The crude product was
chromatographed on silica
gel with 10-20% ethyl acetate/hexanes.
EXAMPLE 1D
tert-butyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(4'-chlorobipheny1-2-
yl)methyl)piperazin-1-yl)benzoate
1H-Pyrrolol2,3-Blpyridine-5-ol (167 mg), EXAMPLE 1C (500 mg), and Cs2CO3
(508 mg) were stirred in dimethylsulfoxide (5 mL) at 130 C for 24 hours. The
mixture was
cooled, diluted with ethyl acetate, washed thee times with water, and brine,
and dried
(Na2SO4), filtered and concentrated. The crude product was chromatographed on
silica gel
with 25% ethyl acetate/hexanes.
EXAMPLE 1E
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(4'-chlorobipheny1-2-
yl)methyl)piperazin-1-
yl)benzoic acid
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EXAMPLE 1D (200 mg) and triethylsilane (1 mL) were stirred in dichloromethane
(15 mL) and trifluoroacetic acid (15 mL) for 1 hour. The mixture was
concentrated, taken up
in ethyl acetate, washed twice with NaH2PO4, and brine, and dried (Na2SO4),
filtered and
concentrated.
EXAMPLE 1F
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-
yl)methylamine
(1.14 g), and triethylamine (1 g) were stirred in tetrahydrofuran (30 mL) for
24 hours. The
solution was diluted with ethyl acetate, washed with NaH2PO4 solution and
brine, and dried
(Na2SO4), filtered and concentrated. The product was triturated from ethyl
acetate.
EXAMPLE 1G
4-14- 1(4'-chloro-1,1'-bipheny1-2-y0methyllpiperazin-1-yll-N-(13-nitro-4-
Rtetrahydro-2H-
pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 1E (115 mg), EXAMPLE 1F (67 mg), 1-ethy1-3-13-
(dimethylamino)propyll-carbodiimide hydrochloride (82 mg), and 4-
dimethylaminopyridine
(26 mg) were stirred in CH2C12 (3 mL) for 24 hours. The reaction was cooled
and
chromatographed on silica gel with 0-5% methanol/ethyl acetate. 1H NMR
(300MHz,
dimethylsulfoxide-d6) 8 11.48 (brs, 1H), 8.34 (br s, 1H), 8.31 (m, 1H), 7.90
(d, 1H), 7.68
(m, 1H), 7.58 (m, 2H), 7.46 (m, 4H), 7.35 (m, 2H), 7.21 (dd, 1H), 6.76 (m,
4H), 6.28
(m, 2H), 3.02 (m, 2H), 2.89 (m, 4H), 2.80 (m, 4H), 2.40 (m, 3H), 1.59 (m, 2H),
1.25 (m, 4H),
0.87 (m, 2H).
EXAMPLE 2
4-14- 1(4'-chloro-1,1'-bipheny1-2-yl)methyllpiperazin-1-yll-N-(14-1(3-
morpholin-4-
ylpropyl)aminol -3 -nitrophenyllsulfony0-2-(1H-pyrrolo12,3 -blpyridin-5 -
yloxy)benzamide
EXAMPLE 2A
4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting 3-(N-morpholiny1)-propylamine for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
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CA 02759182 2015-06-16
'
EXAMPLE 2B
4- { 4-[(4'-chloro-1,1'-bipheny1-2-yl)methyl]piperazin-l-y1) -N-( { 4- [(3-
morpholi n-4-
ylpropypamino1-3-nitrophenyl}sulfony1)-2-(1H-pyrrolo[2,3-b]pyridin-5-
yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 2A for EXAMPLE 1F in
EXAMPLE 10. NMR (300MHz, dimethylsulfoxide-d6) 8 11.60 (brs, 1H), 8.60 (m,
1H),
8.43 (d, 1H), 7.94 (d, 1H), 7.64 (m, 214), 7.54 (d, 1H), 7.45 (m, 4H), 7.33
(m, 2H), 7.23 (dd,
1H), 6.96 (d, 1H), 6.85 (m, 2H), 6.32 (d, 1H), 6.26 (d, 1H), 3.60 (m, 4H),
3.10 (m, 4H), 3.05
(m, 10H), 2.40 (m, 2H), 2.33 (m, 2H), 1.77 (m, 2H).
EXAMPLE 3
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-ylimethyl ipiperazin-l-
y1)-N-({ 3-
nitro-44(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)aminolphenyl )sulfony1)-2-
(1H-
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
EXAMPLE 3A
methyl 4,4-dimethy1-2-(trifluoramethylsulfonyloxy)cyclohex-1-enecarboxylate
To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was
added 5,5-dimethy1-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0 C.
After
stirring for 30 minutes, the mixture was cooled to ¨78 C and
trifluoromethanesulfonic anhydride (40
mL) was added. The reaction mixture was warmed to room temperature and stirred
for 24
hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated to
give the product.
EXAMPLE 3B
methyl 2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enecarboxylate
EXAMPLE 3A (62.15g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and
tetrakis(triphenylphosphine)palladium(0) (2g) in 2:1 dimethoxyethane /methanol
(600 mL)
were heated to 70 C for 24 hours. The mixture was concentrated. Ether (4x 200
mL) was
added and the mixture was filtered. The combined ether solution was
concentrated to give the
product.
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EXAMPLE 3C
(2-(4-chloropheny0-4,4-dimethylcyclohex-1-enyl)methanol
To a mixture of LiBH4 (13g), EXAMPLE 3B (53.8 g) and ether (400 mL), was added
methanol (25 mL) slowly by syringe. The mixture was stirred at room
temperature for 24
hours. The reaction was quenched with 1N HC1 with ice-cooling. The mixture was
diluted
with water and extracted with ether (3x 100 mL). The extracts were dried
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 0-
30% ethyl
acetate/hexanes.
EXAMPLE 3D
tert-butyl 4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-
1-
carboxylate
Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 3C (29.3 g) and
triethylamine (30 mL) in CH2C12 (500 mL) at 0 C, and the mixture was stirred
for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at
room
temperature for 24 hours. The suspension was washed with brine, dried,
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 10-
20% ethyl
acetate/hexanes.
EXAMPLE 3E
14(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
EXAMPLE 3D (1 g) was stirred in dichloromethane (10 mL), trifluoroacetic acid
(10
mL), and triethylsilane (1 mL) for 1 hour. The mixture was concentrated, taken
up in a
mixture of dichloromethane (100 mL) and saturated aqueous Na2CO3 solution (20
mL) and
stirred for 10 minutes. The layers were separated, and the organic layer was
dried over
Na2SO4, filtered, and concentrated to give the product.
EXAMPLE 3F
5-bromo-1-(triisopropylsily0-1H-pyrrolo[2,3-blpyridine
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran
(250
mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and
after 10
minutes, TIPS-C1 (triisopropylchlorosilane ) (18.2 mL) was added. The mixture
was stirred at
room temperature for 24 hours. The reaction was diluted with ether, and the
resulting solution
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was washed twice with water. The extracts were dried (Na2SO4), filtered, and
concentrated.
The crude product was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
EXAMPLE 3G
1-(triisopropylsily1)-1H-pyrrolo1L2,3-blpyridin-5-o1
To a mixture of EXAMPLE 3F (24.3 g) in tetrahydrofuran (500 mL) at -78 C was
added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was
added, and the
mixture was allowed to warm to room temperature over 1 hour. The reaction was
poured into
water, extracted thee times with ethyl acetate, and the combined extracts were
washed with
brine and concentrated. The crude product was taken up in tetrahydrofuran (200
mL) at 0 C,
and 1M NaOH (69 mL) was added, followed by 30% H202 (8.43 mL), and the
solution was
stirred for 1 hour. Na2S203 (10 g) was added, and the pH was adjusted to 4-5
with
concentrated HC1 and solid NaH2PO4. The solution was extracted twice with
ethyl acetate,
and the combined extracts were washed with brine, dried (Na2SO4), filtered,
and
concentrated. The crude product was chromatographed on silica gel with 5-25%
ethyl
acetate/hexanes.
EXAMPLE 3H
methyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-fluorobenzoate
A mixture of EXAMPLE 3G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and
K3PO4
(9.32 g) in diglyme (40 mL) at 115 C was stirred for 24 hours. The reaction
was cooled,
diluted with ether (600 mL), and washed twice with water, and brine, and
concentrated. The
crude product was chromatographed on silica gel with 2-50% ethyl
acetate/hexanes.
EXAMPLE 31
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoate
A mixture of EXAMPLE 3H (1.55 g), EXAMPLE 3E (2.42 g), and HK2PO4 (1.42 g)
in dimethylsulfoxide (20 mL) at 135 C was stirred for 24 hours. The reaction
was cooled,
diluted with ether (400 mL), and washed with 3x 1M NaOH, and brine, and
concentrated.
The crude product was chromatographed on silica gel with 10-50% ethyl
acetate/hexanes.
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EXAMPLE 3J
2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
EXAMPLE 31(200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 500C was
stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and
extracted thee
times with ethyl acetate. The combined extracts were washed with brine, and
concentrated to
give the pure product.
EXAMPLE 3K
tert-butyl 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate
Tert-butyl piperidin-4-ylcarbamate (45.00 g, 225 mmol) and dihydro-2H-pyran-
4(3H)-one (24.74 g, 247 mmol) were added to dichloromethane (1000 mL). Sodium
triacetoxyborohydride (61.90 g, 292 mmol) was added, and the solution was
stirred at room
temperature for 16 hours. The solution was extracted with 1M sodium hydroxide
and dried
over anhydrous sodium sulfate. The solution was filtered and concentrated and
purified by
flash column chromatography on silica gel with 10% methanol (in
dichloromethane)
increasing to 20% methanol (in dichloromethane).
EXAMPLE 3L
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride
A solution of EXAMPLE 3K (52.57 g, 185 mmol) in dichloromethane (900 mL) was
treated with 4M aqueous HC1 (462 mL), and the solution was mixed vigorously at
room
temperature for 16 hours. Solvent was removed under vacuum to give crude
product as the
dihydrochloride salt, which was used without further purification.
EXAMPLE 3M
3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonamide
EXAMPLE 3L (22.12 g, 86 mmol) was added to 1,4-dioxane (300 mL) and water (43
mL). Triethylamine (43.6 mL, 31.6 g, 313 mmol) was added, and the mixture was
stirred at
room temperature until EXAMPLE 3L had completely dissolved. 4-chloro-3-
nitrobenzenesulfonamide was added and the mixture was heated at 90 C for 16
hours. The
mixture was cooled, and the solvents were removed under vacuum. 10% methanol
(in
dichloromethane) was added and the solution was stirred vigorously at room
temperature
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until a fine suspension was obtained. The solid was isolated by vacuum
filtration and washed
with dichloromethane to give pure product.
EXAMPLE 3N
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)aminolphenyl } sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 3M for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.65 (brs, 1H), 8.53 (br s, 1H), 8.18 (m, 1H), 8.00
(br s, 1H), 7.63
(m, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd,
1H), 6.37 (d, 1H),
6.20 (d, 1H), 3.95 (m, 2H), 3.05 (m, 10H), 2.73 (m, 4H), 2.17 (m, 10H), 1.95
(m, 2H), 1.80
(m, 2H), 1.63 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 4
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R1-methylpiperidin-4-yl)aminol -3-nitrophenyl } sulfony1)-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 4A
4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting 4-amino-N-methylpiperidine for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 4B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R1-methylpiperidin-4-yl)aminol -3-nitrophenyl } sulfony1)-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.65 (brs, 1H), 8.55 (br s, 1H), 8.17 (m, 1H), 8.02
(d, 1H), 7.85
(dd, 1H), 7.51 (m, 3H), 7.35 (m, 2H), 7.18 (dd, 1H), 7.05 (d, 2H), 6.68 (dd,
1H), 6.38 (d, 1H),
6.20 (d, 1H), 3.90 (m, 1H), 3.09 (m, 8H), 2.77 (m, 2H), 2.05-2.30 (m, 10H),
1.95 (s, 3H),
1.39 (t, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
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EXAMPLE 5
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl]methyl)piperazin-1-
y1)-N-(13-
-
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl)sulfony1)-2-(1H-
pyrrolo[2,3-
,
b]pyridin-5-yloxy)benzamide
EXAMPLE 5A
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
A mixture of 4-fluoro-3-nitrobenzenesulfonarnide (2.18 g), 1-(tetrahydropyran-
4-
.
yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrafuran (30 mL)
were stirred
overnight, neutralized with concentrated HC1 and concentrated. The residue was
suspended
in ethyl acetate and the precipitates were collected, washed with water and
dried to provide
the title compound.
EXAMPLE 5B
methyl 4,4-dimethy1-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was
added 5,5-dimethy1-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0 C.
After
stirring for 30 minutes, the mixture was cooled to ¨78 C and
trifluoromethanesulfonic anhydride (40
mL) was added. The reaction mixture was warmed to room temperature and stirred
for 24
hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated to
give the product.
EXAMPLE 5C
methyl 2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enecarboxylate
EXAMPLE 5B (62.15g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and
tetralds(triphenylphosphine)palladium(0) (2g) in 2:1 dimethoxyethane /methanol
(600 mL)
were heated to 70 C for 24 hours. The mixture was concentrated. Ether (4x 200
mL) was
added and the mixture was filtered. The combined ether solution was
concentrated to give the
product.
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EXAMPLE 5D
(2-(4-chloropheny0-4,4-dimethylcyclohex-1-enyl)methanol
To a mixture of LiBH4 (13g), EXAMPLE 5C (53.8 g) and ether (400 mL), was added

methanol (25 mL) slowly by syringe. The mixture was stirred at room
temperature for 24
hours. The reaction was quenched with 1N HC1 with ice-cooling. The mixture was
diluted
with water and extracted with ether (3x 100 mL). The extracts were dried
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 0-
30% ethyl
acetate/hexanes.
EXAMPLE 5E
tert-butyl 4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-
1-
carboxylate
Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 5D (29.3 g) and
triethylamine (30 mL) in CH2C12 (500 mL) at 0 C, and the mixture was stirred
for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at
room
temperature for 24 hours. The suspension was washed with brine, dried,
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 10-
20% ethyl
acetate/hexanes.
EXAMPLE 5F
14(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
EXAMPLE 5E (200 mg) and triethylsilane (1 mL) were stirred in dichloromethane
(15 mL) and trifluoroacetic acid (15 mL) for 1 hour. The mixture was
concentrated, taken up
in ethyl acetate, washed twice with NaH2PO4, and brine, and dried (Na2SO4),
filtered and
concentrated.
EXAMPLE 5G
5-bromo-1-(triisopropylsily1)-1H-pyrrolo[2,3-blpyridine
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran
(250
mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and
after 10
minutes, TIPS-C1 (triisopropylchlorosilane ) (18.2 mL) was added. The mixture
was stirred at
room temperature for 24 hours. The reaction was diluted with ether, and the
resulting solution
was washed twice with water. The extracts were dried (Na2504), filtered, and
concentrated.
The crude product was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
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EXAMPLE 5H
1-(triisopropylsily1)-1H-pyrrolo1L2,3-blpyridin-5-o1
To a mixture of EXAMPLE 5G (24.3 g) in tetrahydrofuran (500 mL) at -78 C was
added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was
added, and the
mixture was allowed to warm to room temperature over 1 hour. The reaction was
poured into
water, extracted thee times with ethyl acetate, and the combined extracts were
washed with
brine and concentrated. The crude product was taken up in tetrahydrofuran (200
mL) at 0 C,
and 1M NaOH (69 mL) was added, followed by 30% H202 (8.43 mL), and the
solution was
stirred for 1 hour. Na2S203 (10 g) was added, and the pH was adjusted to 4-5
with
concentrated HC1 and solid NaH2PO4. The solution was extracted twice with
ethyl acetate,
and the combined extracts were washed with brine, dried (Na2SO4), filtered,
and
concentrated. The crude product was chromatographed on silica gel with 5-25%
ethyl
acetate/hexanes.
EXAMPLE 51
methyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-fluorobenzoate
A mixture of EXAMPLE 5H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and
K3PO4
(9.32 g) in diglyme (40 mL) at 115 C was stirred for 24 hours. The reaction
was cooled,
diluted with ether (600 mL), and washed twice with water, and brine, and
concentrated. The
crude product was chromatographed on silica gel with 2-50% ethyl
acetate/hexanes.
EXAMPLE 5J
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-l-y1)benzoate
A mixture of EXAMPLE 51 (1.55 g), EXAMPLE 5F (2.42 g), and HK2PO4 (1.42 g) in
dimethylsulfoxide (20 mL) at 135 C was stirred for 24 hours. The reaction was
cooled,
diluted with ether (400 mL), and washed with 3x 1M NaOH, and brine, and
concentrated.
The crude product was chromatographed on silica gel with 10-50% ethyl
acetate/hexanes.
EXAMPLE 5K
2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
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EXAMPLE 5J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50 C was
stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and
extracted thee
times with ethyl acetate. The combined extracts were washed with brine, and
concentrated to
give the pure product.
EXAMPLE 5L
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 5K (3.39 g), EXAMPLE 5A (1.87 g), I-ethyl-3-113-
(dimethylamino)propyll-carbodiimide hydrochloride (2.39 g), and 4-
dimethylaminopyridine
(1.09 g) were stirred in CH2C12 (40 mL) for 24 hours. The reaction was cooled
and
chromatographed on silica gel with 25-100% ethyl acetate/hexanes, then 10%
methanol/ethyl
acetate with 1% acetic acid,o give the product (1.62 g, 32%) as a white solid.
1H NMR
(300MHz, dimethylsulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d, 1H),
7.89 (dd,
1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H),
6.39 (d, 1H), 6.19
(d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73(m, 2H), 2.18 (m, 6H),
1.95 (m, 2H),
1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).
EXAMPLE 6
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-methylpiperazin-1-yl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-pyrrolo [2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 6A
4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide
A 50 mL round-bottomed flask was charged with 4-chloro-3-
nitrobenzenesulfonamide (1 g, 4.23 mmol), 4-methylpiperazin-1-amine
dihydrochloride (1 g,
5.32 mmol), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (3 mL, 20.01 mmol)
in dioxane
(10 mL). The reaction mixture was refluxed for 12 hours. After this time, the
reaction mixture
was cooled to room temperature, the salt filtered off via a Buchner funnel,
and the solvent
removed in vacuo. The crude product was added to a silica gel column
(Analogix, SF65-
200g) and purified by eluting with 0-5% methanol in dichloromethane.
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EXAMPLE 6B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en-1 -yll methyl }
piperazin-1-y1)-N-( { 4-
R4-methylpiperazin-1-yl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-pyrrolo [2,3-
blpyridin-5-
yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 6A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.65 (brs, 1H), 9.09 (br s, 1H), 8.47 (d, 1H), 8.24
(dd, 1H), 7.99
(d, 1H), 7.50 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.35 (d,
1H), 6.20 (d, 1H),
3.04 (m, 4H), 2.89 (m, 4H), 2.73 (m, 2H), 2.34 (s, 3H), 2.17 (m, 6H), 1.95 (br
s, 2H), 1.38 (t,
2H), 1.05 (m, 4H), 0.93 (s, 6H).
EXAMPLE 7
2-(9H-carbazol-4-yloxy)-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-

yll methyl } piperazin- 1-y1)-N-( { 4- R1-methylpiperidin-4-yl)aminol -3 -
nitrophenyl } sulfonyl)benzamide
EXAMPLE 7A
ethyl 2-(9H-carbazol-4-yloxy)-4-fluorobenzoate
This EXAMPLE was prepared by substituting ethyl 2,4-difluorobenzoate for
methyl
2,4-difluorobenzoate and 4-hydroxycarbazole for EXAMPLE 3G in EXAMPLE 3H.
EXAMPLE 7B
ethyl 2-(9H-carbazol-4-yloxy)-4-(44(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoate
This EXAMPLE was prepared by substituting EXAMPLE 7A for EXAMPLE 3H in
EXAMPLE 31.
EXAMPLE 7C
2-(9H-carbazol-4-yloxy)-4-(44(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-l-yl)benzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 31 in
EXAMPLE 3J, except here upon completion of the reaction, water and 2N HC1 were
added
to adjust the pH to 2, and the HC1 salt of the product was extracted using
CHC13/CH3OH.
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EXAMPLE 7D
2-(9H-carbazol-4-yloxy)-4-(4-{ {2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-

yllmethyl}piperazin-1-y1)-N4 { 4- [(1-methylpiperidin-4-yl)aminol -3 -
nitrophenyl}sulfonyl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 7C for EXAMPLE 1E and
EXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G, except here the purification was done

by preparative HPLC using a C18 column, 250 x 50 mm, 1011, and eluting with a
gradient of
20-100% CH3CN vs. 0.1% trifluoroacetic acid in water, giving the product as a
bistrifluoroacetate salt. 1H NMR (300 MHz, dimethylsulfoxide -d6) 8 11.82 (br
s, 1H),
11.40 (s, 1H), 9.70, 9.40 (both v br s, total 2H), 8.40 (d, 1H), 8.10 (br d,
1H), 7.90 (br d, 1H),
7.72 (dd, 1H), 7.60 (d, 1H), 7.48 (d, 1H), 7.38 (m, 3H), 7.22 (m, 2H), 7.07
(m, 4H), 6.78 (dd,
1H), 6.43 (dd, 1H), 6.19 (s, 1H), 3.97 (m, 1H), 3.80 (m, 2H), 3.60, 3.30,
3.10, 2.80 (all br m,
total 11H), 2.20, 2.10, 2.00 (all br m, total 8H), 1.78 (m, 2H), 1.42 (m, 2H),
1.25 (m, 2H),
0.92 (s, 6H).
EXAMPLE 8
2-(9H-carbazol-4-yloxy)-4-(4-{ {2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-

yllmethyl}piperazin-1-y1)-N-({ 3-nitro-4- R3-pyrrolidin-1-
ylpropyl)aminolphenyl}sulfonyl)benzamide
EXAMPLE 8A
3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide
This EXAMPLE was prepared by substituting 3-(pyrrolidin-1-yl)propan-1-amine
for
1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 8B
2-(9H-carbazol-4-yloxy)-4-(4-{ {2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-

yllmethyl}piperazin-1-y1)-N-({ 3-nitro-4- R3-pyrrolidin-1-
ylpropyl)aminolphenyl}sulfonyl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 7C for EXAMPLE 1E and
EXAMPLE 8A for EXAMPLE 1F in EXAMPLE 1G, except here the purification was done

by preparative HPLC using a C18 column, 250 x 50 mm, 1011, and eluting with a
gradient
of 20-100% CH3CN vs. 0.1% trifluoroacetic acid in water, giving the product as
a
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bistrifluoroacetate salt.. 1H NMR (300 MHz, dimethylsulfoxide -d6) 8 11.80 (br
s, 1H),
11.42 (s, 1H), 9.50, 9.25 (both v br s, total 2H), 8.58 (br t, 1H), 8.43 (d,
1H), 7.91 ( d, 1H),
7.72 ( dd, 1H), 7.60 (d, 1H), 7.50 (d, 1H), 7.38 (m, 3H), 7.23 (m, 2H), 7.07
(m, 3H), 6.93 (d,
1H), 6.78 (dd, 1H), 6.44 (dd, 1H), 6.18 (s, 1H), 3.70, 3.60, 3.20. 3.00 (all
br m, total 18H),
2.18 (br m, 2H), 2.00-180 (envelope, 8H), 1.42 (m, 2H), 0.92 (s, 6H).
EXAMPLE 9
Trans-4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
({ 4- R4-morpholin-4-ylcyclohexyl)aminol -3-nitrophenyl } sulfony0-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 9A
Trans-tert-butyl 4-morpholinocyclohexylcarbamate
A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol), bis(2-
bromoethyl) ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml, 237 mmol)
in N,N-
dimethylformamide (200 ml) was stirred for 16 hours at 70 C. The reaction
mixture was
cooled down to room temperature, concentrated and the product was extracted
with ethyl
acetate. The organic layer was washed with sodium carbonate solution (15%
aq.), dried and
concentrated. The product was used in next step without purification.
EXAMPLE 9B
Trans-4-morpholinocyclohexanamine dihydrochloride
To a solution of trans-tert-butyl-4-morpholinocyclohexylcarbamate (19.2 g,
67.5
mmol) in dichloromethane (100 ml) was added HC1 (100 ml, 400 mmol) (4M in
dioxane) and
the reaction mixture was stirred for 16 hours at room temperature. The
reaction mixture was
diluted with ether and solid salt was filtered off, and dried in an oven.
EXAMPLE 9C
Trans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
A solution of trans-4-morpholinocyclohexanamine dihydrochloride (5 g, 19.44
mmol), 4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) and
triethylamine (20 ml,
143 mmol) in tetrahydrofuran (60 ml) was stirred for 16 hours at room
temperature. The
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solid product was filtered off, washed with tetrahydrofuran, ether,
dichloromethane (3 x) and
dried under vacuum.
EXAMPLE 9D
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
({ 4- [(4-morpholin-4-ylcyclohexyl)aminol -3-nitrophenyl } sulfony1)-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 9C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.61 (brs, 1H), 8.49 (br s, 1H), 8.12 (m, 1H), 7.99
(br s, 1H), 7.71
(m, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H), 7.01 (m, 1H), 6.65 (dd,
1H), 6.36 (d, 1H),
6.21 (d, 1H), 3.60 (m, 4H), 3.04 (m, 4H), 2.73 (m, 2H), 2.57 (m, 2H), 2.42 (m,
1H), 2.18 (m,
6H), 2.05 (m, 2H), 1.95 (m, 2H), 1.90 (m, 2H), 1.38 (m, 6H), 1.15 (m, 3H),
0.92 (s, 6H).
EXAMPLE 10
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
[(2-methoxyethyl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 10A
4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting 2-methoxyethylamine for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 10B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
[(2-methoxyethyl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 10A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.65 (brs, 1H), 8.58-8.49 (m, 1H), 8.55 (d, 1H), 8.03
(d, 1H), 7.79
(m, 1H), 7.49 (m, 3H), 7.34 (m, 2H), 7.06 (m, 1H), 7.04 (d, 2H), 6.68 (dd,
1H), 6.38 (m, 1H),
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6.20 (d, 1H), 3.61-3.51 (m, 4H), 3.31 (s, 3H), 3.07 (m, 4H), 2.74 (m, 2H),
2.17 (m, 6H), 1.95
(br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 11
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(3 -
nitro-4- { R3S)-tetrahydro-2H-pyran-3-ylmethyll amino } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 11A
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide and
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
This EXAMPLE was prepared by substituting (tetrahydro-2H-pyran-3-
yl)methanamine for 1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 11B
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an AD
column (21mm i.d.x 250 mm in length) using a gradient of 10-30% 0.1%
diethylamine
methanol in CO2 over 15 minutes (oven temperature: 40 C; flow rate: 40
mL/minute) to
provide the title compound.
EXAMPLE 11C
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an AD
column (21mm i.d.x 250 mm in length) using a gradient of 10-30% 0.1%
diethylamine
methanol in CO2 over 15 minutes (oven temperature: 40 C; flow rate: 40
mL/minute) to
provide the title compound.
EXAMPLE 11D
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { R35)-tetrahydro-2H-pyran-3-ylmethyll amino } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
To a mixture of EXAMPLE 3J (59.8 mg, 0.105 mmol), EXAMPLE 11B (33mg,
0.105 mmol) and N,N-dimethylpyridin-4-amine (38.4 mg, 0.314 mmol) in
dichloromethane
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(5 ml) was added 1-ethy1-343-(dimethylamino)propy11-carbodiimide hydrochloride
(24.07
mg, 0.13 mmol). The reaction mixture was stirred at room temperature overnight
and
concentrated. The residue was purified by reverse phase HPLC on a C18 column
using a
gradient of 40-60% acetonitrile/0.1% trifluoroacetic acid in water to give the
title compound
as the trifluoroacetate salt. The trifluoroacetic acid salt was dissolved in
dichloromethane (6
ml) and washed with 50% aqueous NaHCO3. The organic layer was dried over
anhydrous
Na2SO4 and concentrated to give the title compound. 1H NMR (500 MHz,
dimethylsulfoxide
-d6) 8 11.68 (s, 1 H), 11.40 (s, br, 1 H), 8.53 - 8.58 (m, 2 H), 8.04 (d, 1
H), 7.80 (dd, 1 H),
7.47 - 7.54 (m, 3 H), 7.34 (d, 2 H), 7.02 - 7.09 (m, 3 H), 6.67 (dd, 1 H),
6.39 (dd, 1 H), 6.19
(d, 1 H), 3.79 (dd, 1 H), 3.69 - 3.73 (m, 1 H), 3.22 - 3.37 (m, 3 H), 3.16 -
3.21 (m, 1 H), 3.07
(s, 4 H), 2.74 (s, 2 H), 2.09 - 2.24 (m, 6 H), 1.95 (s, 2 H), 1.86 - 1.93 (m,
1 H), 1.79 - 1.85 (m,
1 H), 1.58 - 1.64 (m, 1 H), 1.42 - 1.51 (m, 1 H), 1.38 (t, 2 H), 1.25 - 1.34
(m, 1 H), 0.92 (s, 6
H).
EXAMPLE 12
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
(1,4-dioxan-2-ylmethoxy)-3 -nitrophenyl[sulfony1}-2- (1H-pyrrolo [2,3-
b[pyridin-5-
yloxy)benzamide
EXAMPLE 12A
4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
(1,4-Dioxan-2-yl)methanol (380 mg, 3.22 mmol) in tetrahydrofuran (30 ml) was
treated with sodium hydride (60%) (245 mg, 6.13 mmol) at room temperature for
30 minutes.
The reaction mixture was cooled in an ice bath and 4-fluoro-3-
nitrobenzenesulfonamide (675
mg, 3.06 mmol) was added. The resulting mixture was stirred at room
temperature for 2
hours and another portion of sodium hydride (60%) (245 mg, 6.13 mmol) was
added. The
reaction mixture was stirred overnight and quenched with ice water (3 m1). The
cloudy
mixture was filtered and the filtrate was concentrated. The residue was
triturated with
methanol to give the title compound.
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EXAMPLE 12B
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(1,4-dioxan-2-ylmethoxy)-3-nitrophenyllsulfonyl }-2-(1H-pyrrolol2,3-blpyridin-
5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
12A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide -d6) 8 11.67
(s, 1
H), 11.42 (s, br, 1 H), 8.34 (s, 1 H), 8.03 (d, 2 H), 7.48 - 7.55 (m, 3 H),
7.41 (d, 1 H), 7.35 (d,
2 H), 7.04 (d, 2 H), 6.67 (dd, 1 H), 6.39 (dd, 1 H), 6.21 (d, 1 H), 4.20 -
4.28 (m, 2 H), 3.85 -
3.91 (m, 1 H), 3.82 (dd, 1 H), 3.74 - 3.78 (m, 1 H), 3.59 - 3.69 (m, 2 H),
3.41 - 3.51 (m, 2 H),
3.05 - 3.17 (m, 4 H), 2.83 (s, br, 2 H), 2.27 (s, br, 4 H), 2.15 (s, 2 H),
1.96 (s, 2 H), 1.39 (t, 2
H), 0.93 (s, 6 H).
EXAMPLE 13
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-l-
y1)-N- R3-
nitro-4- { R3R)-tetrahydro-2H-pyran-3-ylmethyll amino } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
11C in place of EXAMPLE 11B. The proton NMR spectra of EXAMPLE 13 and
EXAMPLE 11D are identical. 1H NMR (500 MHz, dimethylsulfoxide -d6) 8 11.68 (s,
1 H),
11.40 (s, br, 1 H), 8.53 - 8.58 (m, 2 H), 8.04 (d, 1 H), 7.80 (dd, 1 H), 7.47 -
7.54 (m, 3 H),
7.34 (d, 2 H), 7.02 - 7.09 (m, 3 H), 6.67 (dd, 1 H), 6.39 (dd, 1 H), 6.19 (d,
1 H), 3.79 (dd, 1
H), 3.69 - 3.73 (m, 1 H), 3.22 - 3.37 (m, 3 H), 3.16 - 3.21 (m, 1 H), 3.07 (s,
4 H), 2.74 (s, 2
H), 2.09 - 2.24 (m, 6 H), 1.95 (s, 2 H), 1.86 - 1.93 (m, 1 H), 1.79 - 1.85 (m,
1 H), 1.58 - 1.64
(m, 1 H), 1.42 - 1.51 (m, 1 H), 1.38 (t, 2 H), 1.25 - 1.34 (m, 1 H), 0.92 (s,
6 H).
EXAMPLE 14
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N-(2-
naphthylsulfony1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using naphthalene-
2-sulfonamide (47 mg, 0.227 mmol) in place of EXAMPLE 11B. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 8 11.82 (s, 1 H), 11.69 (s, 1 H), 8.51 (s, 1 H), 8.08
(d, 1 H), 8.05 (d, 1
H), 7.97 (dd, 2 H), 7.82 (dd, 1 H), 7.66 - 7.71 (m, 1 H), 7.63 (t, 1 H), 7.54
(d, 1 H), 7.47 -
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7.52 (m, 2 H), 7.34 (d, 2 H), 7.04 (d, 2 H), 6.65 (dd, 1 H), 6.39 (dd, 1 H),
6.18 (s, 1 H), 3.04
(s, 4 H), 2.72 (s, 2 H), 2.10 - 2.20 (m, 6 H), 1.95 (s, 2 H), 1.38 (t, 2 H),
0.92 (s, 6 H).
EXAMPLE 15
4-(4- { 1L4-(4-chloropheny1)-6,6-dimethyl-5 ,6-dihydro-2H-pyran-3-yll methyl }
piperazin-l-y1)-
N-(1 3-nitro-4- Rtetrahydro-2H-pyran-4-ylmethyBaminolphenyl I sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 15A
methyl 6,6-dimethy1-4-oxotetrahydro-2H-pyran-3-carboxylate
To a suspension of hexane-washed NaH (0.72 g, 60% in mineral oil) in
tetrahydrofuran (30 mL) was added a solution of 2,2-dimethyldihydro-2H-pyran-
4(3H)-one
(2.0 g) in tetrahydrofuran (20mL). The suspension was stirred at room
temperature for 30
minutes. The dimethylcarbonate (6.31 mL) was added dropwise by syringe. The
mixture was
heated to reflux for 4h. LC/MS showed the expected product as the major
product. The
mixture was acidified with 5% HC1 and extracted with dichloromethane (100 mL x
3) and
washed with water, brine and dried over Na2SO4. After evaporation, the crude
product was
loaded on a column and eluted with 10% ethyl acetate in hexane to give the
product.
EXAMPLE 15B
methyl 6,6-dimethy1-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3-
carboxylate
To a cooled (0 C) stirring suspension of NaH (0.983 g, 60% in mineral oil) in
ether
(50 mL) was added EXAMPLE 15A (3.2 g). The mixture was stirred at 0 C for 30
minutes
before the addition of Tf20 (4.2 mL). The mixture was then stirred at room
temperature
overnight. The mixture was diluted with ether (200 mL) and washed with 5% HC1
, water and
brine. After drying over Na2SO4, evaporation of solvent gave the crude product
which was
used in the next step without further purification.
EXAMPLE 15C
methyl 4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate
To a solution of EXAMPLE 15B (2.88 g), 4-chlorophenylboronic acid (1.88 g) and

Pd(Ph3P)4 (0.578 g) in toluene (40 mL) and ethanol (10 mL) was added 2N Na2CO3
(10 mL).
The mixture was stirred at reflux overnight. The mixture was diluted ether
(300 mL) and
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washed with water, brine and dried over Na2SO4. After evaporation of solvent,
the residue
was loaded on a column and eluted with 3% ethyl acetate in hexane to give the
product.
EXAMPLE 15D
(4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol
To a solution of EXAMPLE 15C (1.6 g) in ether (20 mL) was added LiA1H4 (1.2
g).
The mixture was stirred for 4 hours. The mixture was acidified carefully with
5% HC1 and
extracted with ethyl acetate (100 mL x 3) and washed with water, brine and
dried over
Na2SO4. After concentration, the crude product was loaded on a column and
eluted with 10%
ethyl acetate in hexane to give the product.
EXAMPLE 15E
4-(4-chloropheny0-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde
To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 mL) at -78 C
was
added dimethylsulfoxide (6.12 mL). The mixture was stirred at the temperature
for 30
minutes, and then a solution of EXAMPLE 15D (1.2 g) in dichloromethane (10 mL)
was
added . The mixture was stirred at -78 C for 2 hours before the addition of
triethylamine (10
mL). The mixture was stirred overnight and the temperature was allowed to rise
to room
temperature. The mixture was diluted with ether (300 mL) and washed with
water, brine and
dried over Na2SO4. Concentration of the solvent and column purification (5%
ethyl acetate in
hexane) gave the product.
EXAMPLE 15F
methyl 2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)-4-(piperazin-1-yl)benzoate
A mixture of EXAMPLE 3H (20.5 g) and piperazine (37.0 g) in dimethylsulfoxide
(200 mL) was heated to 110 C for 24 hours, and the mixture was allowed to cool
to room
temperature. The mixture was poured into water (1 L), extracted thee times
with
dichloromethane, and the combined extracts were washed with 2x water, and
brine and
filtered and concentrated to give the pure product.
EXAMPLE 15G
methyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(4-(4-chloropheny1)-6,6-
dimethy1-5,6-
dihydro-2H-pyran-3-y0methyl)piperazin-1-y1)benzoate
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To a solution of EXAMPLE 15E (100 mg) and EXAMPLE 15F (177 mg) in
dichloromethane (10 mL) was added sodium triacetoxyborohydride (154 mg). The
mixture
was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and
washed with
2%Na0H, water and brine. After drying over Na2SO4, the mixture was filtered
and the
solvent was evaporated under vacuum. The residue was loaded on a column and
eluted with
30% ethyl acetate in hexane to give the pure product.
EXAMPLE 15H
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-44-(4-chloropheny1)-6,6-dimethyl-5,6-
dihydro-
2H-pyran-3-yl)methyl)piperazin-1-y1)benzoic acid
To a solution of EXAMPLE 15G (254 mg) in tetrahydrofuran (4 mL), methanol (2
mL) and water (2 mL) was added LiOH H20 (126mg). The mixture was stirred
overnight.
The mixture was then neutralized with 5% HC1 and diluted with ethyl acetate
(200 mL). After
washing with brine, it was dried over Na2SO4. Filtration and evaporation of
solvent gave the
product.
EXAMPLE 151
4-(4- { 1L4-(4-chloropheny1)-6,6-dimethyl-5 ,6-dihydro-2H-pyran-3-yll methyl }
piperazin-l-y1)-
N-( { 3-nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G, substituting
EXAMPLE 1E with EXAMPLE 15H. 1H NMR (300 MHz, dimethylsulfoxide -d6) 8 11.68
(br s, 1H), 11.42 (s, 1H), 8.60 (m, 1H), 8.57 (d, 1H), 8.05(d, 1H), 7.80 (dd,
1H), 7.48-7.54
(m, 3H), 7.38 (d, 2H), 7.12 (m, 3H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (s,
1H), 4.11(s, 2H),
3.85(m, 2H), 3.27(m, 6H), 3.07 (m, 2H), 2.84 (m, 2H), 2.14 (m, 5H), 1.92(m,
1H), 1.42 (m,
2H), 1.24(m, 2H), 1.10 (s, 6H).
EXAMPLE 16
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 4-
R2-methoxyethyl)aminol -3 - Rtrifluoromethyl)sulfonyllphenyl I sulfony0-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
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EXAMPLE 16A
4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.536 g, 5 mmol), 2-
methoxyethanamine (0.376 g, 5mmol ), and triethylamine (1.939 g, 15 mmol) in
anhydrous
tetrahydrofuran (30 mL) solution was heated at 55 C for 3 hours. The solution
was diluted
with ethyl acetate, washed with water and brine, and dried (Na2SO4), filtered
and the filtrate
was concentrated. The crude material was used in the next step without further
purification.
EXAMPLE 16B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 4-
[(2-methoxyethyl)amino] -3- Rtrifluoromethyl)sulfonyllphenyl I sulfony0-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 16A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400MHz,
dimethylsulfoxide-d6) 8 11.67 (brs, 1H), 8.14 (m 1H), 8.03 (d, 1H), 7.91 (d,
1H), 7.50
(m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.04 (m, 3H), 6.67 (dd, 1H), 6.39 (m,
1H), 6.19 (d, 1H),
3.51 (m, 4H), 3.28 (s, 3H), 3.06 (m, 4H), 2.75 (m, 2H), 2.17 (m, 6H), 1.95 (m,
2H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 17
4-(4- { [2-(4-chloropheny0-4,4-dimethylc yclohex-1-en-1-yll methyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)-N-({ 4-Rtetrahydro-2H-pyran-4-ylmethyl)aminol-3-

Rtrifluoromethyl)sulfonyllphenyl I sulfonyl)benzamide
EXAMPLE 17A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
This EXAMPLE was prepared by substituting 1-(tetrahydropyran-4-yl)methylamine
for 2-methoxyethanamine in EXAMPLE 16A.
EXAMPLE 17B
4-(4- { [2-(4-chloropheny0-4,4-dimethylc yclohex-1-en-l-yll methyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)-N-({ 4-Rtetrahydro-2H-pyran-4-ylmethyl)aminol-3-

Rtrifluoromethyl)sulfonyllphenyl I sulfonyl)benzamide
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This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E and
EXAMPLE 17A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400MHz,
dimethylsulfoxide-d6) 8 11.70 (brs, 1H), 8.15 (m 1H), 8.04 (d, 1H), 7.92 (d,
1H), 7.51
(m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.05 (m, 3H), 6.68 (dd, 1H), 6.40 (m,
1H), 6.18 (d, 1H),
3.85 (m, 2H), 3,25 (m, 4H), 3.07 (m, 4H), 2.77 (m, 2H), 2.17 (m, 6H), 1.95 (m,
2H), 1.84
(m,1 H), 1.54 (m, 2H), 1.39(t, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
EXAMPLE 18
4-(4-112-(4-chloropheny1)-4,4-dimethylc yclohex-1-en-1-yll methyllpiperazin-l-
y1)-2-(1H-
indo1-5-yloxy)-N-(13-nitro-4-1(tetrahydro-2H-pyran-4-
ylmethyBaminolphenyllsulfonyl)benzamide
EXAMPLE 18A
methyl 2-(1H-indo1-5-yloxy)-4-fluorobenzoate
A mixture of 5-hydroxyindole (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),
and
K3PO4 (9.32 g) in diglyme (40 mL) at 115 C was stirred for 24 hours. The
reaction was
cooled, diluted with ether (600 mL), and washed twice with water, and brine,
and
concentrated. The crude product was chromatographed on silica gel with 2-50%
ethyl
acetate/hexanes.
EXAMPLE 18B
methyl 2-(1H-indo1-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoate
A mixture of EXAMPLE 18A (1.7 g), EXAMPLE 3E (1.8 g), and HK2PO4 (1.21 g) in
dimethylsulfoxide (20 mL) at 135 C was stirred for 24 hours. The reaction was
cooled,
diluted with ether (400 mL), and washed with 3x 1M NaOH, and brine, and
concentrated.
The crude product was chromatographed on silica gel with 10-50% ethyl
acetate/hexanes.
EXAMPLE 18C
2-(1H-indo1-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
EXAMPLE 18B (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 500C was
stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and
extracted thee
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times with ethyl acetate. The combined extracts were washed with brine, and
concentrated to
give the pure product.
EXAMPLE 18D
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
indol-5-yloxy)-N-(13-nitro-4-Rtetrahydro-2H-pyran-4-
ylmethyBaminolphenyl I sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 11D by replacing
EXAMPLE 3J with EXAMPLE 18C, and EXAMPLE 1F for EXAMPLE 11B. 1H NMR
(300MHz, dimethylsulfoxide-d6) 8 11.18 (s, 2H), 8.59-8.64 (m, 2H), 7.80 (dd,
1H), 7.52 (d,
1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H), 7.16 (d, 1H), 7.10 (d,1H), 7.03 (d, 2H),
6.8 (dd, 1H),
6.65 (dd, 1H), 6.40 )s, 1H), 6.14 (d, 1H), 3.85 (dd, 2H), 3.24-3.32 (m, 4H),
3.03 (s, 3H), 2.73
(s, 2H), 2.12-2.17 (m, 5H), 1.68-1.94 (m, 3H), 1.61 (d, 2H), 1.37 (t, 2H),
1.24-1.27 (m, 2H),
0.92 (s, 6H).
EXAMPLE 19
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl
}piperazin-1-y1)-2-
(1H-indo1-5-yloxy)-N-(1 4-R4-morpholin-4-ylcyclohexyl)aminol-3-
nitrophenyl I sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 11D by replacing
EXAMPLE 11B with EXAMPLE 9B and EXAMPLE 3J with EXAMPLE 18C. 1H NMR
(500 MHz, pyridine-d5) 8 12.29 (s, 1H), 9.29 (d, J=2.1 Hz, 1H), 8.37 (d, J=7.6
Hz, 1H), 8.32
(dd, J=9.3, 2.3 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.52 - 7.57 (m, 2H), 7.39 -
7.47 (m, 3H),
7.10 (dd, J=8.7, 2.3 Hz, 1H), 7.05 - 7.08 (m, 2H), 6.90 (d, J=9.5 Hz, 1H),
6.74 (dd, J=9.0, 2.3
Hz, 1H), 6.59 - 6.63 (m, 1H), 6.55 (d, J=2.4 Hz, 1H), 3.72 - 3.78 (m, 4H),
3.33 - 3.43 (m,
1H), 2.99 - 3.09 (m, 4H), 2.76 (s, 2H), 2.46 - 2.54 (m, 4H), 2.16 - 2.29 (m,
3H), 2.09 - 2.14
(m, 4H), 2.05 (d, J=11.9 Hz, 2H), 1.97 (d, J=1.8 Hz, 2H), 1.87 (d, J=11.6 Hz,
2H), 1.19 -
1.42 (m, 6H), 0.93 (s, 6H).
EXAMPLE 20
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
indol-5-yloxy)-N4 { 4- R2-methoxyethyl)aminol-3-nitrophenyl }
sulfonyl)benzamide
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The title compound was prepared as described in EXAMPLE 11D by replacing
EXAMPLE 11B with EXAMPLE 10A and EXAMPLE 3J with EXAMPLE 18C. 1H NMR
(400 MHz, dimethylsulfoxide - d6) 6 11.20 (br. s, 1H) 11.15 (s, 1H) 8.59 (m,
2H) 7.81 (dd,
1H) 7.50 (d, 1H) 7.36 (m, 4H) 7.08 (m, 4H) 6.85 (dd, 1H) 6.65 (dd, 1H) 6.38
(m, 1H) 6.14
(m, 1H) 3.58 (m, 4H) 3.30 (s, 3H) 3.03 (m, 4H) 2.73 (s, 2H) 2.15 (m, 6H) 1.96
(s, 2H) 1.38 (t,
2H) 0.92 (s, 6H)
EXAMPLE 21
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-l-
y1)-2-(1H-
indo1-5-yloxy)-N-11(3-nitro-4-{ 11(3S)-tetrahydro-2H-pyran-3-
ylmethyl] amino } phenyBsulfonyllbenzamide
The title compound was prepared as described in EXAMPLE 11D by replacing
EXAMPLE 3J with EXAMPLE 18C. 1H NMR (400 MHz, dimethylsulfoxide -d6) 8 11.17
(s,
2 H), 8.53 - 8.65 (m, 2 H), 7.80 (d, 1 H), 7.51 (d, 1 H), 7.38 - 7.44 (m, 2
H), 7.33 (d, 2 H),
7.15 (s, 1 H), 7.02 - 7.09 (m, 3 H), 6.82 - 6.92 (m, 1 H), 6.65 (d, 1 H), 6.39
(s, 1 H), 6.14 (s, 1
H), 3.68 - 3.82 (m, 2 H), 3.22 - 3.32 (m, 2 H), 3.13 - 3.22 (m, 1 H), 3.03 (s,
4 H), 2.72 (s, 2
H), 2.09 - 2.23 (m, 6 H), 1.78 - 1.98 (m, 4 H), 1.56 - 1.66 (m, 1 H), 1.43 -
1.51 (m, 1 H), 1.37
(t, 2 H), 1.22 - 1.33 (m, 1 H), 0.92 (s, 6 H).
EXAMPLE 22
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
indo1-5-yloxy)-N-R3-nitro-4- { R3R)-tetrahydro-2H-pyran-3-
ylmethyl] amino } phenyBsulfonyllbenzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
11C in place of EXAMPLE 11B, and EXAMPLE 18C in place of EXAMPLE 3J. 1H NMR
(400 MHz, dimethylsulfoxide -d6) 8 11.17 (s, 2 H), 8.53 - 8.65 (m, 2 H), 7.80
(d, 1 H), 7.51
(d, 1 H), 7.38 - 7.44 (m, 2 H), 7.33 (d, 2 H), 7.15 (s, 1 H), 7.02 - 7.09 (m,
3 H), 6.82 - 6.92
(m, 1 H), 6.65 (d, 1 H), 6.39 (s, 1 H), 6.14 (s, 1 H), 3.68 - 3.82 (m, 2 H),
3.22 - 3.32 (m, 2 H),
3.13 - 3.22 (m, 1 H), 3.03 (s, 4 H), 2.72 (s, 2 H), 2.09 - 2.23 (m, 6 H), 1.78
- 1.98 (m, 4 H),
1.56 - 1.66 (m, 1 H), 1.43 - 1.51 (m, 1 H), 1.37 (t, 2 H), 1.22 - 1.33 (m, 1
H), 0.92 (s, 6 H).
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EXAMPLE 23
4-(4-114-(4-chloropheny1)-6,6-dimethy1-5,6-dihydro-2H-pyran-3-
yllmethyllpiperazin-1-y1)-
2-(1H-indol-5-yloxy)-N-(13-nitro-4-1(tetrahydro-2H-pyran-4-
ylmethyBaminolphenyllsulfonyl)benzamide
EXAMPLE 23A
methyl 2-(1H-indo1-5-yloxy)-4-(piperazin-1-y1)benzoate
The title compound was prepared as described in EXAMPLE 15F by replacing
EXAMPLE 3H with EXAMPLE 18A.
EXAMPLE 23B
methyl 2-(1H-indo1-5-yloxy)-4-(44(4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-
2H-pyran-
3-y1)methyl)piperazin-1-y1)benzoate
The title compound was prepared as described in EXAMPLE 15G by replacing
EXAMPLE 15F with EXAMPLE 23A.
EXAMPLE 23C
2-(1H-indo1-5-yloxy)-4-(44(4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-
pyran-3-
y1)methyl)piperazin-1-y1)benzoic acid
The title compound was prepared as described in EXAMPLE 15H by replacing
EXAMPLE 15G with EXAMPLE 23B.
EXAMPLE 23D
4-(4-114-(4-chloropheny1)-6,6-dimethy1-5,6-dihydro-2H-pyran-3-
yllmethyllpiperazin-1-y1)-
2-(1H-indo1-5-yloxy)-N-(13-nitro-4-1(tetrahydro-2H-pyran-4-
ylmethyBaminolphenyllsulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 11D by replacing
EXAMPLE 11B with EXAMPLE 1F, and EXAMPLE 3J with EXAMPLE 23C. 1H NMR
(400 MHz, dimethylsulf oxide -d6) 8 11.20 (br s, 1H), 11.17(s, 1H), 8.63 (t, 1
H),
8.59 (d, 1 H), 7.79 (dd, 1 H), 7.51 (d, 1 H), 7.36 (m, 3 H), 7.13 (m, 2 H),
6.86 (dd, 1 H), 6.66
(dd, 1 H), 6.39 (s, 1 H), 6.15 (d, 1 H), 4.10 (s, 2 H), 3.85 (m, 3 H), 3.50
(m, 2 H), 3.42 (m, 2
H), 3.24 (m, 4 H), 3.02 (m, 4 H), 2.82 (m, 2 H), 2.16 (m, 2 H), 1.61 (m, 3 H),
1.25 (m, 4 H),
1.17 (s, 6 H).
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EXAMPLE 24
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-113-
nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyll sulfony11-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 24A
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) was
treated
with 60% NaH (1.377 g). The solution was stirred for 20 minutes at the room
temperature. To
this solution was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-
wise. The
reaction was stirred for another 2 hours. The mixture was poured into water,
neutralized with
10% HC1, and extracted with ethyl acetate thee times. The combined organic
layers were
washed with brine, dried over MgSO4, filtered, and concentrated. The residue
was purified
with flash column chromatography on silica gel eluting with 20-60% ethyl
acetate in hexanes.
EXAMPLE 24B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-113-
nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyll sulfony11-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.33 (s,
1H), 8.00-8.02 (m, 2H), 7.50-7.53 (m, 3H), 7.34-7.36 (m, 3H), 7.04 (d, 2H),
6.67 (dd, 1H),
6.38 (d, 1H), 6.21 (s, 1H), 4.06 (d, 2H), 3.88 (dd, 2H), 3.08 (s, 4H), 2.80
(s, 2H), 2.25 (s, 4H),
2.15 (s, 2H), 1.96 (s, 2H), 1.63-1.66 (m, 2H), 1.52-1.55 (m, 1 H), 1.33-1.40
(m, 4H), 0.92 (s,
6H).
EXAMPLE 25
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(1,4-dioxan-2-ylmethyl)aminol -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
EXAMPLE 25A
4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide
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The title compound was prepared as described in EXAMPLE 1F using (1,4-dioxan-2-

yl)methanamine in place of (tetrahydropyran-4-yl)methanamine.
EXAMPLE 25B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(1,4-dioxan-2-ylmethyl)aminol -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
25A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.66
(s,
1H), 11.38 (s, 1H), 8.53 - 8.59 (m, 2H), 8.03 (d, 1H), 7.81 (dd, 1H), 7.46 -
7.54 (m, 3H), 7.34
(d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.19 (d,
1H), 3.75 - 3.86 (m,
3H), 3.58 - 3.68 (m, 2H), 3.45 - 3.52 (m, 2H), 3.35 - 3.43 (m, 2H), 3.07 (s,
4H), 2.75 (s, 2H),
2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H)
EXAMPLE 26
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
nitro-4-1(2,2,2-trifluoroethyBaminolphenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 26A
3-nitro-4-(2,2,2-trifluoroethylamino)benzenesulfonamide
The title compound was prepared by substituting 2,2,2-trifluoroethanamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 26B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
nitro-4-1(2,2,2-trifluoroethyBaminolphenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 6 11.48 (s, 1H),
8.40 (m,
2H), 7.90 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H), 7.40 (t, 1H), 7.34 (d, 2H),
7.25 (d, 1H), 7.06
(m, 3H), 6.61 (dd, 1H), 6.26 (m, 2H), 4.32 (m, 2H), 3.00 (m, 4H), 2.73 (s,
2H), 2.19 (m, 6H),
1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 27
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyllpiperazin-1-
y1)-N-(13-
nitro-4-1(3 ,3,3-trifluoropropyl)aminolphenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 27A
3-nitro-4-(3,3,3-trifluoropropylamino)benzenesulfonamide
The title compound was prepared by substituting 3,3,3-trifluoropropan-1-amine
for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 27B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyllpiperazin-1-
y1)-N-(13-
nitro-4-1(3 ,3,3-trifluoropropyl)aminolphenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 27A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 6 11.47 (s, 1H),
8.37 (d,
1H), 8.29 (m, 1H), 7.89 (d, 1H), 7.61 (m, 2H), 7.39 (t, 1H), 7.35 (d, 2H),
7.22 (d, 1H), 7.05
(d, 2H), 6.75 (d, 1H), 6.62 (dd, 1H), 6.27 (m, 2H), 3.59 (q, 2H), 3.00 (m,
4H), 2.73 (s, 2H),
2.66 (m, 2H), 2.18 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (m, 6H).
EXAMPLE 28
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(2S)-1,4-dioxan-2-ylmethoxyl -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5 -
yloxy)benzamide
EXAMPLE 28A
(S)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
The racemic mixture of EXAMPLE 12A was resolved on a SFC chiral AD column to
provide the title compound.
EXAMPLE 28B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(2S)-1,4-dioxan-2-ylmethoxyl -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5 -
yloxy)benzamide
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The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
28A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.67
(s,
2H), 8.35 (s, 1H), 8.03 (d, 2H), 7.48 - 7.57 (m, 3H), 7.42 (d, 1H), 7.35 (d,
2H), 7.05 (d, 2H),
6.68 (dd, 1H), 6.39 (dd, 1H), 6.21 (s, 1H), 4.19 - 4.30 (m, 2H), 3.85 - 3.92
(m, 1H), 3.73 -
3.85 (m, 2H), 3.58 - 3.70 (m, 2H), 3.40 - 3.52 (m, 2H), 3.10 (s, 4H), 2.85 (s,
2H), 2.18 - 2.39
(m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 29
Cis-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
[(4- { [(4-methoxycyclohexyl)methyllamino}-3-nitrophenyl)sulfonyfl -2-(1H-
pyrrolo [2,3 -
b[pyridin-5 -yloxy)benzamide
EXAMPLE 29A
Cis-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 34A (1 g) in
tetrahydrofuran (20 mL) was treated with N,N-diisopropylethylamine (0.871 mL)
overnight.
The reaction mixture was concentrated and the residue was purified by reverse
phase
chromatography, eluted with 40-55% acetonitrile in 0.1% trifluoroacetic acid
in water over
min to give the cis isomer EXAMPLE 29A and trans isomer EXAMPLE 34B.
EXAMPLE 29B
Cis-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
[(4- { [(4-methoxycyclohexyl)methyllamino}-3-nitrophenyl)sulfonyfl -2-(1H-
pyrrolo [2,3 -
b[pyridin-5 -yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
29A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69
(s,
1H), 11.36 (s, 1H), 8.53 - 8.63 (m, 2H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.47 -
7.56 (m, 3H), 7.34
(d, 2H), 7.00 - 7.12 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.37
(s, 1H), 3.26 (t,
2H), 3.20 (s, 3H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H),
1.81 (dd, 2H), 1.64 -
1.74 (m, 1H), 1.48 (dd, 2H), 1.23 - 1.42 (m, 6H), 0.92 (s, 6H).
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EXAMPLE 30
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-(14-
[(2R)-1,4-dioxan-2-ylmethoxy1-3-nitrophenyllsulfony1)-2-(1H-pyrrolo [2,3-
b[pyridin-5-
yloxy)benzamide
EXAMPLE 30A
(R)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
The racemic mixture of EXAMPLE 12A was resolved on a SFC chiral AD column to
provide the title compound.
EXAMPLE 30B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-(14-
[(2R)-1,4-dioxan-2-ylmethoxy1-3-nitrophenyllsulfony1)-2-(1H-pyrrolo [2,3-
b[pyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
30A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.67
(s,
2H), 8.35 (s, 1H), 8.03 (d, 2H), 7.48 - 7.57 (m, 3H), 7.42 (d, 1H), 7.35 (d,
2H), 7.05 (d, 2H),
6.68 (dd, 1H), 6.39 (dd, 1H), 6.21 (s, 1H), 4.19 - 4.30 (m, 2H), 3.85 - 3.92
(m, 1H), 3.73 -
3.85 (m, 2H), 3.58 - 3.70 (m, 2H), 3.40 - 3.52 (m, 2H), 3.10 (s, 4H), 2.85 (s,
2H), 2.18 - 2.39
(m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 31
4-(4-{ [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl[methyl}piperazin-1-y1)-
N-({ 4- [(1,4-dioxan-2-ylmethyl)amino1-3-nitrophenyl}sulfony1)-2-(1H-pyrrolo
[2,3-b[pyridin-
5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 25A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.66 (s, 1H), 11.46 (m, 1H), 8.54
(m, 2H),
8.45 (m, 1H), 8.03 (d, 1H), 7.83 (m, 2H), 7.50 (m, 3H), 7.34 (m, 3H), 7.12 (m,
2H), 6.68 (dd,
1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.11 (s, 2H), 3.79 (m, 4H), 3.51 (m, 6H),
3.05 (m, 4H), 2.17
(m, 3H), 1.17 (s, 6H).
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EXAMPLE 32
4-(4- { [4-(4-chloropheny0-6,6-dimethyl-5 ,6-dihydro-2H-pyran-3-
yl[methyl}piperazin-1-y1)-
N- { [4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl[sulfonyl}-2-(1H-pyrrolo [2,3 -
b[pyridin-5 -
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 12A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H), 8.37 (d, 1H), 8.03 (m,
2H), 7.50
(m, 3H), 7.37 (d, 2H), 7.13 (d, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d,
1H), 4.25 (m, 2H),
4.12 (s, 2H), 3.84 (m, 3H), 3.63 (m, 2H), 3.45 (m, 2H), 3.06 (m, 4H), 2.86 (m,
2H), 2.24 (m,
6H), 1.20 (m, 6H).
EXAMPLE 33
Trans-4-(4- { [4-(4-chloropheny0-6,6-dimethyl-5,6-dihydro-2H-pyran-3 -
yl[methyl}piperazin-
1-y1)-N-( { 4- [(4-morpholin-4-ylcyclohexyl)amino1-3-nitrophenyl}sulfony1)-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 9C, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.63 (s, 1H), 8.51 (d, 1H), 8.15 (d,
1H), 8.01
(d, 1H), 7.76 (dd, 1H), 7.48 (m, 3H), 7.38 (d, 2H), 7.13 (d, 2H), 7.06 (d,
1H), 6.66 (dd, 1H),
6.36 (dd, 1H), 6.21 (d, 1H), 4.11 (s, 2H), 3.63 (m, 5H), 3.05 (m, 4H), 2.83
(s, 2H), 2.64 (m,
4H), 2.17 (m, 6H), 2.05 (m, 2H), 1.91 (s, 2H), 1.43 (m, 6H), 1.17 (m, 6H).
EXAMPLE 34
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
[(4- { [(4-methoxycyclohexyl)methyl[amino}-3-nitrophenyl)sulfony11-2-(1H-
pyrrolo [2,3 -
b[pyridin-5-yloxy)benzamide
EXAMPLE 34A
(4-methoxycyclohexyl)methanamine
(4-Methoxyphenyl)methanamine (1 g, 1.29 mmol) in ethanol (10 ml) was treated
with
5% Rh-A1203 (99.8 mg, 0.048 mmol) under H2 atmosphere (500 psi) at 50 C for 16
hours.
Additional 5% Rh-A1203(0.4 g) was added. The resulting mixture was stirred
under H2
atmosphere (500 psi) at 60 C for 2 hours. The insoluble material was filtered
off and the
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filtrate was concentrated to provide a mixture of cis and trans product as an
oil, which was
used in the next step without further purification.
EXAMPLE 34B
Trans-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 34A (1 g) in
tetrahydrofuran (20 mL) was treated with N,N-diisopropylethylamine (0.871 mL)
overnight.
The reaction mixture was concentrated and the residue was purified by reverse
phase
chromatography, and was eluted with 40-55% acetonitrile in 0.1%
trifluoroacetic acid in
water over 25 minutes.
EXAMPLE 34C
Trans-4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
R4- { R4-methoxycyclohexyl)methyll amino } -3 -nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
34B in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69
(s, 1
H), 11.37 (s, 1 H), 8.52 - 8.62 (m, 2 H), 8.04 (d, 1 H), 7.79 (dd, 1 H), 7.47 -
7.55 (m, 3 H),
7.34 (d, 2 H), 7.02 - 7.09 (m, 3 H), 6.68 (dd, 1 H), 6.39 (dd, 1 H), 6.19 (d,
1 H), 3.21 - 3.27
(m, 5 H), 3.02 - 3.12 (m, 5 H), 2.75 (s, 2 H), 2.20 (s, 4 H), 2.14 (s, 2 H),
1.93 - 2.04 (m, 4 H),
1.79 (d, 2 H), 1.55 - 1.65 (m, 1 H), 1.38 (t, 2 H), 0.97 - 1.12 (m, 4 H), 0.92
(s, 6 H).
EXAMPLE 35
4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5 ,6-dihydro-2H-pyran-3-yll methyl }
piperazin-l-y1)-
N- { [5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfonyl } -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 36C, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.65 (s, 1H), 8.78 (s, 1H), 8.58 (s,
1H), 8.00
(d, 1H), 7.51 (m, 3H), 7.38 (d, 2H), 7.14 (d, 2H), 6.68 (dd, 1H), 6.37 (dd,
1H), 6.23 (d, 1H),
4.31 (d, 2H), 4.13 (s, 2H), 3.88 (dd, 2H), 3.11 (m, 5H), 2.16 (m, 6H), 1.65
(m, 2H), 1.35 (m,
2H), 1.19 (s, 6H).
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EXAMPLE 36
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N- { 115 -
cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yfl sulfonyl } -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 36A
5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL) was
cooled to 0 C. To this solution was added 7N NH3 in methanol (80 mL). The
reaction
mixture was stirred overnight. The solvent was removed at low temperature, and
the residue
was partitioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl
acetate thee times. The combined organic layers were washed with brine, dried
(MgSO4),
filtered, and concentrated. The solid was purified by flash column
chromatography on silica
gel using 20-100% ethyl acetate in hexanes to give the title compound.
EXAMPLE 36B
The title compound was prepared by substituting EXAMPLE 36A for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 36C
A mixture of EXAMPLE 36B (0.702 g), dicyanozinc (0.129 g), and
tetrakis(triphenylphosphine)palladium(0) (0.231 g) in N,N-dimethylformamide (2
mL) was
degassed via vacuum/nitrogen cycle thee times. The reaction mixture was heated
at 120 C
for 3 hours. After cooling, it was poured into water and extracted with ethyl
acetate thee
times. The combined organic layers were washed with brine, dried over MgSO4,
filtered, and
concentrated. The residue was purified with flash column chromatography on
silica gel
eluting with 20%-60% ethyl acetate in hexanes to give the title compound.
EXAMPLE 36D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { 115 -
cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yfl sulfonyl } -2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.56 (s, 1H),
8.66 (s,
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1H), 8.44 (s, 1H), 7.94 (d, 1H), 7.55 (d, 1H), 7.44 (t, 1H), 7.34-7.35 (m,
3H), 7.04 (d, 2H),
6.65 (dd, 1H), 6.32 (s, 1H), 6.24 (s, 1H), 4.26 (d, 2H), 3.86 (dd, 2H), 3.10
(s, 4H), 2.75 (s,
2H), 2.31-2.35 (m, 2H), 2.01-2.05 (m, 1H), 2.15 (s, 2H), 1.96 (s, 2H), 1.63-
1.66 (m, 2H),
1.33-1.40 (m, 4H), 0.92 (s, 6H).
EXAMPLE 37
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(4-fluorotetrahydro-2H-pyran-4-y0methoxyl -3 -nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 37A
1,6-dioxaspiro12.5loctane-2-carbonitrile
A mixture of tetrahydropyran-4-one (10 mL) and chloroacetonitrile (6.4 mL) in
tert-
butanol (10 mL) was stirred for 10 minutes. To this solution was added a
solution of
potassium tert-butoxide (12.11 g) in 200 mL of tert-butanol at room
temperature over 40
minutes. The reaction mixture was stirred for 16 hours, diluted with water and
quenched
slowly with 1 N HC1. The solvent was partially removed by rotary evaporation.
It was then
extracted with ether (5x 200 mL). The combined extracts was washed with brine,
dried over
MgSO4, filtered, and the filtrate was concentrated and purified by flash
chromatography on
silica with 3:7 to 1:1 ethyl acetate:hexanes to provide the title compound.
EXAMPLE 37B
2-(4-fluorotetrahydro-2H-pyran-4-y1)-2-hydroxyacetonitrile
EXAMPLE 37A (11.5 g) in dichloromethane (40 mL) in a polypropylene bottle was
treated with 70% hydrogen fluoride-pyridine (10.4 mL) dropwise at 0 C. The
solution was
allowed to warm to room temperature over 3 hours, and stirred for an
additional 1.5 hours.
The reaction mixture was diluted with ethyl acetate (200 mL) and poured into
saturated
aqueous NaHCO3. Additional solid NaHCO3 was used carefully until bubbling
ceased. The
organic layer was isolated, and the aqueous layer was extracted with
additional ethyl acetate
three times (150 mL each).The combined organic layers were washed with 5% HC1
(50 mL
each, twice), brine, dried over MgSO4, filtered and concentrated to give the
desired product
which was used directly in the next step.
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EXAMPLE 37C
(4-fluorotetrahydro-2H-pyran-4-yl)methanol
EXAMPLE 37B (11.7 g, 74 mmol) in 2-propanol (150 mL) and water (37.5 mL) was
cooled to 0 C. To this solution was added NaBH4 (4.20 g, 111 mmol). The
solution was
stirred and allowed to warm to room temperature over 3 hours. It was quenched
with
acetone, and stirred for another 1 hour. The clear liquid was separated from
solid by
decanting. Additional ethyl acetate (2x 100 mL) was used to wash the solid,
and the mixture
was decanted. The combined organic solutions were concentrated. The residue
was purified
by flash chromatography, eluting with 1:1 ethyl acetate:hexanes to provide the
title
compound.
EXAMPLE 37D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 37C for (tetrahydro-2H-

pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 37E
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 4-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl -3 -nitrophenyl}sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
37D in place of EXAMPLE 11B. 1H NMR (dimethylsulfoxide-d6). 11.64 (s, 2H),
8.33 (s,
1H), 8.00-8.01 (m, 2H), 7.39-7.57 (m, 4H), 7.33 (d, J = 8.24 Hz, 2H), 7.03 (d,
J = 8.54 Hz,
2H), 6.65 (dd, J = 9, 1.98 Hz, 1H), 6.37-6.38 (m, 1H), 6.19 (d, J = 1.53 Hz,
1H), 4.35 (d, J =
20.75 Hz, 2H), 3.74-3.78 (m, 2H), 3.55-3.60 (m, 2H), 3.07 (br, 4H), 2.80 (br,
2H), 2.25 (br,
4H), 2.13 (br, 2H), 1.81-1.94 (m, 6H), 1.38 (t, J = 6.26 Hz, 2H), 0.91 (s,
6H).
EXAMPLE 38
N- { 113-(aminocarbony1)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyllsulfonyll-4-
(4- { 11244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 38A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
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The title compound was prepared by substituting 3-cyano-4-
fluorobenzenesulfonamide for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE
24A.
EXAMPLE 38B
5-sulfamoy1-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide
To a solution of EXAMPLE 38A (0.455 g) in ethanol (3 mL) and tetrahydrofuran
(1
mL) was added hydrogen peroxide (30% in water, 2 mL) followed by 1 N aqueous
NaOH
(1.024 ml) and heated to 35 C for 3 hours. The reaction was poured into
dichloromethane
(50 mL) and 1N aqueous HC1 (25 mL). The aqueous layer was extracted with
dichloromethane (3 x 50 mL). The precipitate contained in the combined organic
layers was
collected by filtration to give the title compound.
EXAMPLE 38C
N- { 113-(aminocarbony1)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyllsulfonyll-4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 38B for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.79 - 11.70 (m, 1H), 11.66 - 11.54 (m, 1H), 9.29 -
9.08 (m, 1H),
8.27 (d, 1H), 8.08 (d, 1H), 7.97 - 7.90 (m, 1H), 7.76 - 7.72 (m, 1H), 7.62 (s,
1H), 7.54 (s, 1H),
7.50 (d, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.08 (d, 1H), 6.74 - 6.67 (m, 1H),
6.44 (s, 1H), 6.22
(s, 1H), 4.03 (d, 6H), 3.74 - 3.52 (m, 4H), 3.33 (s, 4H), 3.11 - 2.90 (m, 2H),
2.01 (s, 4H), 1.79
- 1.58 (m, 2H), 1.24 (s, 5H), 0.94 (s, 6H).
EXAMPLE 39
Cis-4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-N-
(1 4- 11(4-morpholin-4-ylcyclohexyl)aminol -3-nitrophenyllsulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 39A
Cis-tert-butyl-4-morpholinocyclohexylcarbamate
To a solution of morpholine (4.08 g) and tert-butyl 4-oxocyclohexylcarbamate
(10 g)
stirred for 24 hours at room temperature in titanium (IV) isopropoxide (27.5
mL), methanol
(10 mL) was added followed by careful addition of sodium borohydride (3.55 g).
The
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reaction mixture was quenched with water/NaOH solution, extracted with ether,
dried over
magnesium sulfate, filtered, and concentrated. The product was separated from
the trans
isomer and purified by flash chromatography (silica gel, 50% - 100% acetone in
hexanes) to
provide the title compound.
EXAMPLE 39B
cis-4-morpholinocyclohexanamine bis(2,2,2-trifluoroacetate)
To a solution of EXAMPLE 39A (2.43 g) in dichloromethane (15 ml) was added
trifluoroacetic acid (5 ml) and the reaction mixture was stirred for 16 hours
at room
temperature. The reaction mixture was concentrated and the crude product was
used without
purification.
EXAMPLE 39C
4-(cis-4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
A solution of EXAMPLE 39B (0.40 g), 4-fluoro-3-nitrobenzenesulfonamide (0.478
g)
and triethylamine (2 mL) in tetrahydrofuran (10 mL) was stirred for 3 days at
room
temperature. The reaction mixture was concentrated and purified by flash
chromatography
(silica gel, 0-30% methanol / dichloromethane) providing the product.
EXAMPLE 39D
Cis -4-(4-1 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll
methyllpiperazin-1-y1)-N-
(14- R4-morpholin-4-ylcyclohexyl)aminol -3-nitrophenyllsulfony1)-2-(1H-pyrrolo
[2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 39C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.07 (s, 1H), 9.30 (d,
1H), 8.64
(d, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.67 (t, 2H), 7.44 (d,
2H), 7.06 (d, 2H),
6.91 (d, 1H), 6.74 (dd, 1H), 6.48 - 6.55 (m, 2H), 3.65 - 3.73 (m, 5H), 3.02 -
3.09 (m, 4H),
2.76 (s, 2H), 2.41 - 2.48 (m, 4H), 2.25 (t, 2H), 2.09 - 2.16 (m, 5H), 1.97 (s,
2H), 1.77 - 1.86
(m, 2H), 1.55 - 1.63 (m, 6H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 40
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-115-
chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yllsulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 40A
5,6-dichloropyridine-3-sulfonamide
The title compound was prepared by substituting 5,6-dichloropyridine-3-
sulfonyl
chloride for 5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 36A.
EXAMPLE 40B
5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 40C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-115-
chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yllsulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.52 (s,
1H), 8.39 (d, 1H), 8.03 (d, 1H), 7.54 (d, 1H), 7.52 (d, 1H), 7.50 (dd, 1H),
7.35 (d, 2H), 7.04
(d, 2H), 6.67 (dd, 1H), 6.39 (m, 1H), 6.21 (d, 1H), 4.25 (d, 2H), 3.87 (dd,
2H), 3.30 (m, 2H),
3.10 (v br s, 4H), 2.90 (v br s, 2H), 2.35 (v br s, 4H), 2.17 (br m, 2H), 2.05
(m, 1H), 1.96 (s,
2H), 1.64 (d, 2H), 1.40 (t, 2H), 1.35 (ddd, 2H), 0.93 (s, 6H).
EXAMPLE 41
4-(4-114-(4-chloropheny0-6,6-dimethy1-5,6-dihydro-2H-pyran-3-
yllmethyllpiperazin-1-y1)-
N-115-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfony11-2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 15H for EXAMPLE 3J
and EXAMPLE 40B for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz,
dimethylsulfoxide-d6) 8 11.68 (s, 1H), 8.55 (d, 1H), 8.41 (d, 1H), 8.04 (d,
1H), 7.54 (m, 2H),
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7.50 (dd, 1H), 7.38 (d, 2H), 7.14 (d, 2H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.20
(d, 1H), 4.25 (d,
2H), 4.12 (s, 2H), 3.87 (dd, 2H), 3.30 (m, 2H), 3.10 (v br s, 4H), 2.90 (v br
s, 2H), 2.27 (v br
s, 4H), 2.17 (br m, 2H), 2.05 (m, 1H), 1.96 (s, 2H), 1.64 (d, 2H), 1.35 (ddd,
2H), 0.97 (s, 6H).
EXAMPLE 42
4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
Amethyl}piperazin-1-y1)-
2-(1H-pyrrolo1L2,3-b[pyridin-5-yloxy)-N-{ [4- [fletrahydro-2H-pyran-4-
ylmethyBamino1-3-
(trifluoromethyl)phenyl] sulfonyllbenzamide
EXAMPLE 42A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-
(trifluoromethyl)benzenesulfonamide
A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056 g),
(tetrahydro-
2H-pyran-4-yl)methanamine (0.5 g) and N,N-diisopropylethylamine (1.68 g) in
anhydrous
dimethylsulfoxide ( 15 mL) solution was heated at 90 C overnight. The reaction
mixture was
cooled to room temperature and diluted with ethyl acetate. The organic phase
was washed
with water, brine, dried over anhydrous sodium sulfate, filtered and
concentrated to afford the
title compound.
EXAMPLE 42B
4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
Amethyl}piperazin-1-y1)-
2-(1H-pyrrolo[2,3-b[pyridin-5-yloxy)-N-{ [4- [fletrahydro-2H-pyran-4-
ylmethyBamino1-3-
(trifluoromethyl)phenyl] sulfonyllbenzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 42A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.73 (s, 1H), 11.25 (s, 1H), 8.08
(d, 1H), 7.89
(d, 1H), 7.77 (m, 1H), 7.61 (d, 1H), 7.51 (m, 2H), 7.37 (d, 2H), 7.13 (d, 2H),
6.88 (d, 1H),
6.67 (dd, 1H), 6.53 (m, 1H), 6.43 (m, 1H), 6.15 (d, 1H), 4.11 (s, 2H), 3.82
(dd, 2H), 3.19 (m,
5H), 3.05 (m, 4H), 2.82 (s, 2H), 2.20 (m, 7H), 1.85 (m, 1H), 1.56 (m, 2H),
1.18 (s, 6H).
EXAMPLE 43
4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
Amethyl}piperazin-1-y1)-
2-(1H-pyrrolo[2,3-b[pyridin-5-yloxy)-N-({ 4- [fletrahydro-2H-pyran-4-
ylmethyBamino1-3-
Rtrifluoromethyl)sulfonyllphenyllsulfonyl)benzamide
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The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 17A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.48 (m, 1H), 8.16
(d, 1H), 8.05
(d, 1H), 7.92 (dd, 1H), 7.52 (m, 3H), 7.37 (d, 2H), 7.27 (m, 1H), 7.11 (m,
3H), 6.68 (dd, 1H),
6.41 (dd, 1H), 6.18 (d, 1H), 4.11 (s, 2H), 3.84 (dd, 2H), 3.25 (m, 4H), 3.07
(m, 4H), 2.84 (m,
2H), 2.23 (m, 5H), 1.84 (m, 1H), 1.55 (m, 2H), 1.25 (m, 3H), 1.18 (s, 6H).
EXAMPLE 44
Trans-4-(4- { 1L4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3 -yll
methyl } piperazin-
1-y1)-N-(14-R4-morpholin-4-ylcyclohexyl)aminol-3-
Rtrifluoromethyl)sulfonyllphenyl I sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -
yloxy)benzamide
EXAMPLE 44A
Trans-4-(4-morpholinocyclohexylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
The title compound was prepared as described in EXAMPLE 16A by replacing 2-
methoxyethanamine with EXAMPLE 9B.
EXAMPLE 44B
Trans-4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3 -yll
methyl } piperazin-
1-y1)-N-(14-R4-morpholin-4-ylcyclohexyl)aminol-3-
Rtrifluoromethyl)sulfonyllphenyl I sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 44A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.62 (s, 1H), 8.08 (s, 1H), 8.00 (d,
1H), 7.85
(d, 1H), 7.47 (m, 3H), 7.38 (d, 2H), 7.14 (d, 2H), 6.98 (d, 1H), 6.65 (dd,
1H), 6.55 (m, 1H),
6.37 (m, 1H), 6.21 (d, 1H), 4.12 (s, 2H), 3.54 (m, 6H), 3.04 (m, 4H), 2.83 (s,
2H), 2.57 (m,
3H), 2.24 (m, 6H), 1.91 (m, 5H), 1.34 (m, 4H), 1.20 (s, 6H).
EXAMPLE 45
4-(4- { [4-(4-chloropheny1)-6,6-dimethyl-5 ,6-dihydro-2H-pyran-3-yll methyl }
piperazin-l-y1)-
N-( { 4- R1-methylpiperidin-4-yl)aminol -3- Rtrifluoromethyl)sulfonyllphenyl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
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EXAMPLE 45A
4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
The title compound was prepared as described in EXAMPLE 16A by replacing 2-
methoxyethanamine with 1-methy1-4-aminopiperidine.
EXAMPLE 45B
4-(4- { 1L4- (4-chloropheny1)-6,6-dimethy1-5 ,6-dihydro-2H-pyran-3-yll methyl
} piperazin-1 -y1)-
N-( { 4- R1-methylpiperidin-4-yl)aminol -3- Rtrifluoromethyl)sulfonyllphenyl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 45A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.59 (s, 1H), 8.10 (s, 1H), 7.98 (d,
1H), 7.90
(dd, 1H), 7.49 (m, 3H), 7.39 (m, 3H), 7.14 (d, 2H), 7.02 (d, 1H), 6.65 (dd,
2H), 6.36 (dd, 1H),
6.22 (d, 1H), 4.12 (s, 2H), 3.75 (m, 1H), 3.16 (m, 4H), 2.98 (m, 5H), 2.88 (m,
5H), 2.67 (s,
2H), 2.22 (m, 6H), 1.68 (m, 1H), 1.18 (s, 6H).
EXAMPLE 46
541[444- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl
}piperazin-1-y1)-2-
(1H-pyrrolo [2,3 -blpyridin-5 -yloxy)benzoyll amino I sulfony1)-2-(tetrahydro-
2H-pyran-4-
ylmethoxy)nicotinamide
5-sulfamoy1-2-((tetrahydro-2H-pyran-4-yl)methoxy)nicotinamide
To EXAMPLE 36C (0.025 g) in ethanol (1 mL) and tetrahydrofuran (1 mL) was
added hydrogen peroxide (30% in water, 0.5 mL) followed by 1M aqueous sodium
hydroxide
(0.056 ml) then another 1 mL of tetrahydrofuran. The reaction was heated to 45
C for 2
hours, cooled, quenched with 1N aqueous HC1 (5 mL), and the product extracted
into
dichloromethane (10 mL). The organic layer was dried over magnesium sulfate,
filtered and
concentrated to give the title compound.
EXAMPLE 46B
541[444- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl
}piperazin-1-y1)-2-
(1H-pyrrolo [2,3 -blpyridin-5 -yloxy)benzoyll amino I sulfony1)-2-(tetrahydro-
2H-pyran-4-
ylmethoxy)nicotinamide
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The title compound was prepared by substituting EXAMPLE 46A for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz, CDC13) 6
10.31 ¨ 10.09 (m, 1H), 9.09 (s, 2H), 8.93 ¨ 8.81 (m, 1H), 8.28 ¨ 8.18 (m, 1H),
8.03 ¨ 7.87
(m, 1H), 7.77 ¨ 7.68 (m, 1H), 7.59 ¨ 7.51 (m, 1H), 7.48 ¨ 7.41 (m, 1H), 6.91
(d, 2H), 6.59 ¨
6.48 (m, 2H), 5.97 (s, 2H), 4.50 (d, 2H), 4.08 ¨ 3.98 (m, 2H), 3.45 (s, 4H),
3.13 ¨ 2.99 (m,
4H), 2.82 ¨ 2.68 (m, 2H), 2.19 (s, 4H), 1.86 (s, 5H), 1.61 ¨ 1.35 (m, 4H),
0.94 (s, 6H).
EXAMPLE 47
N-(15-bromo-6-R1-methylpiperidin-4-yl)methoxylpyridin-3-yll sulfony1)-4-(4- {
[244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 47A
5-bromo-6-((1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamide
To (1-methylpiperidin-4-yl)methanol (0.109 g) in tetrahydrofuran (2 mL) was
added
sodium hydride (0.136 g). After 30 minutes, EXAMPLE 36A (0.230 g) was added as
a
solution in tetrahydrofuran (1 mL) and the reaction was heated to 50 C. After
4 hours, the
reaction was cooled, poured into water (10 mL) and dichloromethane (50 mL),
and the pH
was adjusted to pH-8. The aqueous layer was extracted with dichloromethane (3
x 50 mL),
and the organic layers were combined, washed with brine (30 mL), dried over
magnesium
sulfate, filtered, and concentrated to give the title compound.
EXAMPLE 47B
N-(15-bromo-6-R1-methylpiperidin-4-yl)methoxylpyridin-3-yll sulfony1)-4-(4- {
[244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.51 (s, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.93 (d,
1H), 7.60 (d, 1H),
7.44 ¨ 7.40 (m, 1H), 7.33 (dd, 3H), 7.05 (d, 2H), 6.61 (d, 1H), 6.31 (dd, 1H),
6.24 (s, 1H),
4.25 (d, 2H), 3.40 (s, 4H), 3.01 (s, 4H), 2.73 (d, J= 8.2, 5H), 2.20 (s, 6H),
1.93 (d, 4H), 1.54
(s, 1H), 1.39 (s, 2H), 1.24 (s, 2H), 0.93 (s, 6H).
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EXAMPLE 48
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
R1-methylpiperidin-4-y1)methoxyl -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 48A
4-((1-methylpiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (1-methylpiperidin-4-
yl)methanol
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 48B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
R1-methylpiperidin-4-y1)methoxyl -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.54 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.87 ¨ 7.77
(m, 1H), 7.58 (d,
1H), 7.43 (s, 1H), 7.40 ¨ 7.00 (m, 7H), 6.70 ¨ 6.56 (m, 1H), 6.31 (s, 1H),
6.24 (s, 1H), 4.05
(s, 2H), 3.46 ¨ 3.33 (m, 2H), 3.02 (s, 6H), 2.72 (d, 5H), 2.21 (s, 6H), 1.96
(s, 5H), 1.70 ¨ 1.48
(m, 2H), 1.39 (s, 2H), 0.93 (s, 6H).
EXAMPLE 49
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-115-
cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yll sulfony11-2-(1H-pyrrolo12,3-
blpyridin-5 -
yloxy)benzamide
EXAMPLE 49A
6-((1, 4-dioxan-2-yl)methoxy)-5-bromopyridine-3-sulfonamide
The title compound was prepared by substituting (1, 4-dioxan-2-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 49B
6-((1,4-dioxan-2-yl)methoxy)-5-cyanopyridine-3-sulfonamide
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The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 49C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-115-
cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yllsulfonyll-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 49B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.50 (s, 1H),
8.60 (s,
1H), 8.40 (s, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H), 7.35 (d, 2H),
7.28 (s, 1H), 7.06 (d,
2H), 6.64 (dd, 1H), 6.29 (m, 2H), 4.40 (d, 2H), 3.90 (m, 1H), 3.79 (m, 2H),
3.63 (m, 2H),
3.46 (m, 4H), 3.07 (s, 4H), 2.85 (m, 2H), 2.34 (m, 4H), 2.16 (m, 2H), 1.40 (t,
2H), 0.93 (s,
6H).
EXAMPLE 50
N-115-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yllsulfony11-4-(4-112-(4-
chloropheny1)-
4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-l-y1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 811.60 (s, 1H), 8.46
(s,
1H), 8.27 (s, 1H), 7.99 (d, 1H), 7.56 (d, 1H), 7.46 (m, 2H), 7.35 (d, 2H),
7.05 (d, 2H), 6.65
(dd, 1H), 6.36 (dd, 1H), 6.22 (d, 1H), 4.34 (m, 2H), 3.88 (m, 1H), 3.79 (m,
2H), 3.63 (m, 2H),
3.46 (m, 2H), 3.06 (s, 4H), 2.81 (s, 2H), 2.26 (m, 4H), 2.15 (s, 2H), 1.96 (s,
2H), 1.38 (m,
2H), 0.93 (s, 6H).
EXAMPLE 51
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(2,2-dimethyltetrahydro-2H-pyran-4-y1)methoxyl -3 -nitrophenyllsulfony1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 51A
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol.
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EXAMPLE 51B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(2,2-dimethyltetrahydro-2H-pyran-4-y1)methoxyl -3 -nitrophenyllsulfony1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
51A in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.69
(s,
2H), 8.35 (s, 2H), 8.03 (d, 4H), 7.47 - 7.58 (m, 6H), 7.31 - 7.42 (m, 6H),
7.04 (d, 4H), 6.68
(dd, 2H), 6.40 (s, 2H), 6.20 (d, 2H), 3.96 - 4.09 (m, 2H), 3.54 - 3.68 (m,
2H), 3.09 (s, 4H),
2.83 (s, 2H), 2.09 - 2.37 (m, 7H), 1.96 (s, 2H), 1.55 - 1.69 (m, 2H), 1.39 (t,
2H), 1.19 (m,
8H), 0.92 (s, 6H).
EXAMPLE 52
N-(13-chloro-5-cyano-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-
4-(4-112-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 52A
3-cyano-4-fluorobenzenesulfonamide
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) in 1,4-dioxane (10 mL) at
0 C
was treated dropwise with a 7 M ammonia solution in methanol (3.57 mL) and
stirred for 30
minutes. A small amount of solid was removed by filtration and discarded. The
filtrate was
concentrated, diluted with ethyl acetate, washed with water and brine, dried
(MgSO4),
filtered, concentrated and triturated with diethyl ether to give the product.
EXAMPLE 52B
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 52A for 4-chloro-3-
nitrobenzenesulfonamide and (tetrahydro-2H-pyran-4-yl)methanamine for 4-
methylpiperazin-l-amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 52C
3-chloro-5-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
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EXAMPLE 52B (0.148 g) in acetonitrile (5 mL) was treated with N-
chlorosuccinimide (0.080 g), heated at 60 C for 3 hours and filtered to
remove a small
amount of solid. The filtrate was concentrated and chromatographed on silica
gel with 3-
15% ethyl acetate in dichloromethane as eluent. The obtained solid was
slurried in water,
filtered, rinsed with additional water and dried under vacuum to give the
product.
EXAMPLE 52D
N-(13-chloro-5-cyano-4- Rtetrahydro-2H-pyran-4-ylmethyBaminolphenyllsulfony1)-
4-(4-1 [2-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 52C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.70 (s, 1H),
11.41
(br s, 1H), 8.07 (d, 1H), 7.89 (s, 2H), 7.61 (m, 1H), 7.53 (m, 2H), 7.35 (d,
2H), 7.18 (m, 1H),
7.05 (d, 2H), 6.69 (m, 1H), 6.42 (dd, 1H), 6.18 (dd, 1H), 3.83 (m, 2H), 3.55
(t, 2H), 3.23 (m,
3H), 3.06 (m, 4H), 2.15 (m, 4H), 1.92 (m, 4H), 1.60 (m, 2H), 1.40 (m, 2H),
1.19 (m, 4H),
0.93 (s, 6H).
EXAMPLE 53
N-(14- R1-acetylpiperidin-4-yl)aminol -3-nitrophenyllsulfony1)-4-(4-1[2-(4-
chloropheny1)-
4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-pyrrolo [2,3 -
blpyridin-5 -
yloxy)benzamide
EXAMPLE 53A
N- R4-chloro-3-nitrophenyl)sulfonyll-4-(4-1[2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-en-
1-yllmethyllpiperazin-1-y1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G.
EXAMPLE 53B
N-(14- R1-acetylpiperidin-4-yl)aminol-3-nitrophenyllsulfony1)-4-(4-1[2-(4-
chloropheny1)-
4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-l-y1)-2-(1H-pyrrolo [2,3 -
blpyridin-5 -
yloxy)benzamide
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A 5 mL round-bottomed flask was charged with EXAMPLE 53A (120 mg), 1-
acetylpiperidin-4-amine (28 mg), and triethylamine (0.064 mL) in dioxane (2
ml). The
reaction mixture was heated to 90 C for 24 hours. The reaction mixture was
cooled to room
temperature, and added to a silica gel column and purified by eluting with 0-
5% methanol in
dichloromethane. 1H NMR (300MHz, dimethylsulfoxide-d6) 8 11.66 (br s, 1H),
8.65 (d, 1H),
8.24 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.54-7.46 (m, 3H), 7.35 (d, 2H),
7.19 (d, 1H), 7.04
(d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 4.28 (d, 1H), 3.97-3.75
(m, 2H), 3.07 (br s,
4H), 2.87-2.70 (m, 4H), 2.29-2.10 (m, 6H), 2.02 (s, 3H), 2.00-1.89 (m, 4H),
1.66-1.54 (m,
2H), 1.39 (t, 2H), 0.92 (s, 6H).
EXAMPLE 54
N-(12-chloro-5-fluoro-4- Rtetrahydro-2H-pyran-4-ylmethyBaminolphenyllsulfony1)-
4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 54A
2-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting 2-chloro-4,5-
difluorobenzenesulfonamide for 4-chloro-3-nitrobenzenesulfonamide and
(tetrahydro-2H-
pyran-4-yl)methanamine for 4-methylpiperazin-1-amine dihydrochloride in
EXAMPLE 6A.
EXAMPLE 54
N-(12-chloro-5-fluoro-4- Rtetrahydro-2H-pyran-4-
ylmethyl)aminolphenyllsulfony1)-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.76 (s, 1H),
11.31
(s, 1H), 8.08 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.55 (m, 2H), 7.34 (d, 2H),
7.04 (d, 2H),
6.90 (s, 1H), 6.84 (d, 1H), 6.69 (dd, 1H), 6.45 (dd, 1H), 6.13 (d, 1H), 3.82
(dd, 2H), 3.24 (t,
2H), 3.05 (m, 6H), 2.73 (s, 2H), 2.14 (m, 6H), 1.95 (s, 2H), 1.81 (m, 1H),
1.61 (m, 2H), 1.38
(t, 2H), 1.17 (m, 2H), 0.92 (s, 6H).
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EXAMPLE 55
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(3 -morpholin-4-ylpropyl)aminol -3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.66 (br s, 1H), 8.75 (t, 1H), 8.54 (d, 1H), 8.03 (d,
1H), 7.79 (dd,
1H), 7.54-7.48 (m, 3H), 7.35 (d, 2H), 7.08-7.02 (m, 3H), 6.67 (dd, 1H), 6.38
(m, 1H), 6.20 (d,
1H), 3.61 (t, 4H), 3.43 (q, 2H), 3.29 (m, 2H), 3.06 (br s, 4H), 2.73 (br s,
2H), 2.47 (br s, 4H),
2.18 (m, 6H), 1.95 (br s, 2H), 1.80 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 56
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(15-
cyano-6-1(4-fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yllsulfony1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 56A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 37C for tetrahydro-2H-
pyran-4-yl)methanol and EXAMPLE 36A for 4-fluoro-3-nitrobenzenesulfonamide in
EXAMPLE 24A.
EXAMPLE 56B
The title compound was prepared by substituting EXAMPLE 56A for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 56C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(15-
cyano-6-1(4-fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yllsulfony1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 56B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.58 (s,
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1H), 8.70 (s, 1H), 8.51 (s, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.45 (t, 1H),
7.35-7.37 (m, 3H),
7.06 (d, 2H), 6.67 (dd, 1H), 6.33 (d, 1H), 6.26 (s, 1H), 4.56 (d, 2H), 3.76-
3.80 (s, 2H), 3.56-
3.62 (m, 2H), 3.01-3.10 (m, 4H), 2.14-2.18 (m, 2H), 1.96 (s, 2H), 1.80-1.87
(m, 4H), 1.41 (t,
2H), 0.93 (s, 6H).
EXAMPLE 57
4-(4-{ 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ 115-
cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yllsulfonyl }-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 57A
5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting 2-morpholinoethanol for
tetrahydro-
2H-pyran-4-yl)methanol and EXAMPLE 36A for 4-fluoro-3-nitrobenzenesulfonamide
in
EXAMPLE 24A.
EXAMPLE 57B
5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 57A for EXAMPLE
36A in EXAMPLE 36B.
EXAMPLE 57C
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ 115-
cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yllsulfonyl }-2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 57B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.56 (s, 1H),
8.64 (s,
1H), 8.41 (s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.36 (d, 2H),
7.31 (s, 1H), 7.06 (d,
2H), 6.65 (dd, 1H), 6.31 (d, 1H), 6.27 (d, 1H), 4.59 (t, 2H), 3.59 (s, 4H),
3.08 (s, 4H), 2.89 (s,
2H), 2.65 (s, 4H), 2.16-2.18 (m, 2H), 1.97 (s, 2H), 1.41 (t, 2H), 0.93 (s,
6H).
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EXAMPLE 58
N- 11(3 -chloro-4- { 112-(2-methoxyethoxy)ethyllsulfonyl}phenyl)sulfonyll -4-
(4- { 11244-
chloropheny0-4,4-dimethylcyclohex-1-en-1-yll methyl}piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 58A
3-chloro-4-(2-(2-methoxyethoxy)ethylthio)benzenesulfonamide
In a 25 mL microwave tube was added sodium hydride (0.6 g) in terahydrofuran
(10
mL) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added
slowly. After
stirring for 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54 g)
dissolved in 10 mL
tetrahydrofuran was added slowly. The mixture was heated at 110 C for 30
minutes in a
Biotage Initiator microwave reactor. Water was added, the product was
extracted with ether
(20 mL x3), dried over Na2SO4, filtered, and the solvent was removed under
reduced
pressure. The crude product was purified by flash chromatography on silica
eluting with 0-
25% ethyl acetate in hexane.
EXAMPLE 58B
3-chloro-4-(2-(2-methoxyethoxy)ethylsulfonyl)benzenesulfonamide
EXAMPLE 58A (0.15 g) was suspended in acetic acid (3 mL). Peracetic acid (0.4
mL) was added slowly. The mixture was stirred at room temperature overnight,
then poured
into Na2S203 solution, and the product precipitated. After filtration and
washing with water,
the product was dried under vacuum.
EXAMPLE 58C
N- 11(3 -chloro-4- { 112-(2-methoxyethoxy)ethyllsulfonyl}phenyl)sulfonyll -4-
(4- { 11244-
chloropheny0-4,4-dimethylcyclohex-1-en-1-yll methyl}piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 6 11.52 (s, 1H),
7.92 (d,
1H), 7.84 (m, 2H), 7.68 (m, 1H), 7.62 (d, 1H), 7.42 (t, 1H), 7.35 (d, 2H),
7.29 (m, 1H), 7.05
(d, 2H), 6.62 (dd, 1H), 6.32 (m, 1H), 6.26 (d, 1H), 3.74 (t, 2H), 3.68 (t,
2H), 3.24 (m, 2H),
3.06 (m, 5H), 3.01 (m, 4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.96 (s, 2H), 1.39 (t,
2H), 0.93 (s,
6H).
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EXAMPLE 59
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f [2-(2-methoxyethoxy)ethyl] sulfonyl I -3 -nitrophenyl)sulfonyl] -2-(1H-
pyrrolo [2,3 -blpyridin-
5-yloxy)benzamide
EXAMPLE 59A
4-(2-(2-methoxyethoxy)ethylthio)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
nitrobenzenesulfonamide
for 3-chloro-4-fluorobenzenesulfonamide in EXAMPLE 58A.
EXAMPLE 59B
4-(2-(2-methoxyethoxy)ethylsulfony1)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 59A for EXAMPLE
58A in EXAMPLE 58B.
EXAMPLE 59C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f [2-(2-methoxyethoxy)ethyl] sulfonyl I -3 -nitrophenyl)sulfonyl] -2-(1H-
pyrrolo [2,3 -blpyridin-
5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 59B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 6 11.51 (s, 1H),
8.17 (m,
1H), 7.94 (m, 3H), 7.64 (d, 1H), 7.42 (m, 1H), 7.35 (d, 2H), 7.28 (d, 1H),
7.05 (d, 2H), 6.62
(m, 1H), 6.28 (m, 2H), 3.83 (m, 4H), 3.16 (m, 2H), 3.08 (s, 3H), 3.01 (m, 4H),
2.73 (s, 2H),
2.18 (m, 6H), 1.96 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H)
EXAMPLE 60
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
({ 4- [(4-morpholin-4-ylcyclohexyl)oxy1-3-nitrophenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 60A
Trans-4-(4-aminocyclohexyloxy)-3-nitrobenzenesulfonamide
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To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) in
tetrahydrofuran (5 mL) was added sodium hydride (0.186 g). After stifling for
15 minutes, 4-
fluoro-3-nitrobenzenesulfonamide (0.256 g) was added as a solution in
tetrahydrofuran (1
mL). The reaction was heated to 60 C for 1.5 hours, cooled, and poured into a
mixture of
dichloromethane (100 mL) and water (25 m1). The aqueous layer was adjusted to
pH-4 with
1N aqueous HC1 and the organic layer was separated, washed with brine (50 ml),
dried over
magnesium sulfate, filtered, and concentrated. The residue was loaded onto
silica gel
(GraceResolv 40 g) and eluted using a gradient of 0.5% to 7.5%
methanol/dichloromethane
over 30 minutes. This solid was treated with HC1 (4.0M in dioxane, 5 ml) at
room
temperature for 1 hour and concentrated to give the title compound.
EXAMPLE 60B
4-(trans-4-morpholinocyclohexyloxy)-3-nitrobenzenesulfonamide
To EXAMPLE 60A (0.220 g) and 1-bromo-2-(2-bromoethoxy)ethane (0.177 g) in
N,N-dimethylformamide (3 mL) was added triethylamine (0.338 ml) and the
reaction heated
to 70 C for 5 hours. The reaction was cooled and the resulting precipitate was
removed by
filtration. The reaction was concentrated and loaded onto silica gel and was
eluted using a
gradient of 0.5% to 7.5% methanol/dichloromethane to give the title compound.
EXAMPLE 60C
Trans-4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll
methyllpiperazin-l-y1)-N-
(14- 1(4-morpholin-4-ylcyclohexyl)oxyl-3-nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.62 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.96 ¨ 7.88
(m, 1H), 7.54 (d,
1H), 7.48 (s, 2H), 7.34 (d, 3H), 7.04 (d, 2H), 6.72 ¨ 6.58 (m, 1H), 6.37 (s,
1H), 6.21 (s, 1H),
4.69 ¨ 4.47 (m, 1H), 3.66 (s, 4H), 3.05 (s, 4H), 2.76 (s, 6H), 2.22 (s, 9H),
1.96 (s, 4H), 1.39
(s, 6H), 0.92 (s, 6H).
EXAMPLE 61
N-(15 -bromo-6-1(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)aminolpyridin-3 -
yllsulfony1)-4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
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EXAMPLE 61A
5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)pyridine-3-
sulfonamide
A mixture of EXAMPLE 36A (1.0 g), EXAMPLE 3L (0.95 g) and triethylamine
(3.08 mL) in anhydrous dioxane (20 mL) was heated at 110 C overnight. The
organic solvent
was removed under vacuum. The residue was purified with flash column
chromatography on
silica gel eluting with 2%-8% methanol/dichloromethane to give the title
compound.
EXAMPLE 61B
N-(15-bromo-6- R1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)aminolpyridin-3-yl I
sulfony0-4-
(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 61A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.59 (s, 1H),
8.35 (s,
1H), 8.00 (s, 2H), 7.55 (d, 1H), 7.46 (m, 2H), 7.34 (d, 2H), 7.04 (d, 2H),
6.63 (dd, 1H), 6.49
(m, 1H), 6.36 (s, 1H), 6.20 (s, 1H), 4.05 (m, 1H), 3.94 (d, 2H), 3.28 (m, 6H),
3.01 (s, 4H),
2.72 (s, 2H), 2.16 (m, 6H), 1.93 (m, 4H), 1.80 (m, 4H), 1.57 (m, 2H), 1.38 (t,
2H), 1.17 (t,
2H), 0.90 (s, 6H).
EXAMPLE 62
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 4-
R2-cyanoethyl)aminol -3 -nitrophenyl } sulfony0-2-(1H-pyrrolo [2,3 -blpyridin-
5-
yloxy)benzamide
EXAMPLE 62A
4-(2-cyanoethylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 3-aminopropanenitrile for
EXAMPLE 39B in EXAMPLE 39C.
EXAMPLE 62B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(1 4-
l(2-c yanoethyl)aminol -3 -nitrophenyl I sulfony0-2-(1H-pyrrolo [2,3-blpyridin-
5-
yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 62A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (501 MHz, pyridine-d5) 8 13.04 (s, 1H), 9.24 (d,
1H), 9.04
(t, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.13 (d, 1H), 7.64 - 7.68 (m, 2H), 7.44
(ddd, 2H), 7.07
(ddd, 2H), 7.02 (d, 1H), 6.76 (dd, 1H), 6.55 (d, 1H), 6.48 (dd, 1H), 3.83 (q,
2H), 3.07 (d, 4H),
2.98 (t, 2H), 2.77 (s, 2H), 2.26 (s, 2H), 2.11 - 2.17 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.93 (s,
6H).
EXAMPLE 63
Cis-4-(4-{ [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yllmethyl
}piperazin-1-
y1)-N-(1 4- R4-morpholin-4-ylcyclohexyl)aminol-3-nitrophenyl I sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 15H for EXAMPLE 3J
and EXAMPLE 39C for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (501 MHz, pyridine-
d5) 8 13.09 (s, 1H), 9.30 (d, 1H), 8.64 (d, 1H), 8.43 (d, 1H), 8.38 (dd, 1H),
8.10 (d, 1H), 7.68
(dt, 2H), 7.46 (ddd, 2H), 7.12 (ddd, 2H), 6.91 (d, 1H), 6.72 (dd, 1H), 6.51
(dd, 1H), 6.49 (d,
1H), 5.69 (s, 2H), 4.40 (s, 2H), 3.69 - 3.73 (m, 4H), 3.68 (s, 1H), 2.95 -
3.02 (m, 4H), 2.84 (s,
2H), 2.40 - 2.46 (m, 4H), 2.21 (s, 2H), 2.08 - 2.15 (m, 5H), 1.76 - 1.84 (m,
2H), 1.55 - 1.63
(m, 6H), 1.29 (s, 6H).
EXAMPLE 64
Trans-N- { [44 { 4- lbis(cyclopropylmethyl)aminolcyclohexyl } amino)-3-
nitrophenyllsulfonyl I -
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 64A
tert-butyl (trans)-4-(bis(cyclopropylmethyl)amino)cyclohexylcarbamate
The title compound was prepared by substituting cyclopropanecarbaldehyde for
4'-
chlorobipheny1-2-carboxaldehyde and tert-butyl (trans)-4-
aminocyclohexylcarbamate for tert-
butyl piperazine-l-carboxylate in EXAMPLE 1A.
EXAMPLE 64B
(trans)-N1,N1-bis(cyclopropylmethyl)cyclohexane-1,4-diamine dihydrochloride
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To a solution of EXAMPLE 64A (1.4 g) in dichloromethane (10 ml) was added
hydrogen chloride (10 ml, 4M in dioxane) and the reaction was stirred for 16
hours at room
temperature. The reaction mixture was diluted with ether and pure product was
filtered off.
EXAMPLE 64C
Trans-4-(4-(bis(cyclopropylmethyl)amino)cyclohexylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE
39B in EXAMPLE 39C.
EXAMPLE 64D
Trans -N- { [44 { 4- lbis(cyclopropylmethyl)aminolcyclohexyl } amino)-3-
nitrophenyll sulfonyl I -
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylc yclohex-1-en-1-yll methyl }
piperazin-l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 64C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.30 (d,
1H), 8.44
(d, 1H), 8.41 (dd, 1H), 8.37 (d, 1H), 8.12 (d, 1H), 7.67 (d, 2H), 7.44 (d,
2H), 7.07 (d, 2H),
7.00 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 3.36 - 3.43 (m, 1H),
3.02 - 3.09 (m,
4H), 2.87 - 2.94 (m, 1H), 2.77 (s, 2H), 2.47 (d, 4H), 2.25 (t, 2H), 2.11 -
2.16 (m, 4H), 2.08 (d,
2H), 1.97 (s, 2H), 1.84 (d, 2H), 1.39 (t, 2H), 1.26 - 1.35 (m, 4H), 0.90 -
0.98 (m, 8H), 0.50 -
0.56 (m, 4H), 0.18 - 0.23 (m, 4H).
EXAMPLE 65
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f R1-methylpiperidin-4-yl)methyll amino I -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 65A
4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 4-aminomethyl-1-methyl
piperidine
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
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EXAMPLE 65B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(1-methylpiperidin-4-yOmethyllaminol-3-nitrophenyOsulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 65A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, dichloromethane-d2) 8 9.57 (bs, 1H),
8.78
(d, 1H), 8.41 (d, 1H), 8.14 (d, 1H), 7.90 (m, 2H), 7.64 (d, 1H), 7.45 (d, 1H),
7.23 (d, 2H),
6.95 (d, 2H), 6.76 (d, 1H), 6.59 (dd, 1H), 6.51 (d, 1H), 6.09 (d, 1H), 3.21
(m, 2H), 3.08 (m,
4H), 3.02 (m, 2H), 2.74 (s, 2H), 2.33 (s, 3H), 2.21-2.17 (m, 6H), 2.16-2.02
(m, 3H), 1.97
(br.s, 2H), 1.78 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 66
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
Rmorpholin-3 -ylmethyl)aminol -3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 66A
tert-butyl 3-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
'The title compound was prepared by substituting tert-butyl 3-
(aminomethyl)morpholine-4-carboxylate for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
EXAMPLE 66B
tert-butyl 3-((4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yObenzoyOsulfamoy1)-2-
nitrophenylamino)methyOmorpholine-4-carboxylate
The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1F, with the exception that the
product
was purified on a silica gel column eluted with 4% methanol in
dichloromethane.
EXAMPLE 66C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(morpholin-3-ylmethyl)aminol-3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
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A solution of EXAMPLE 66B in 50% trifluoroacetic acid and dichloromethane
mixture was stirred at ambient temperature for 2 hours. The solvents were
evaporated and
the residue was purified on a reverse phase HPLC using a gradient of 20-80%
acetonitrile in
water containing 10 mM ammonium acetate. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
11.61 (s, 1H), 8.52 (bs, 1H), 8.49 (d, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.54
(d, 1H), 7.46
(s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (dd, 1H), 6.34 (s,
1H), 6.21 (d, 1H),
3.89 (d, 1H), 3.76 (d, 1H), 3.55-3.46 (m, 2H), 3.40-3.35 (m, 4H), 3.04 (m,
4H),2.91 (t, 1H),
2.73 (s, 2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 67
4-(4-{ 1L4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yllmethyl}piperazin-1-y1)-
N-(1 4- R4-methylpiperazin-1-yl)aminol -3-nitrophenyl I sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 6A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.58 (s, 1H), 9.04 (s, 1H), 8.44 (d,
1H), 7.97
(d, 1H), 7.76 (dd, 1H), 7.49 (m, 4H), 7.38 (d, 2H), 7.14 (d, 2H), 6.64 (dd,
1H), 6.34 (d, 1H),
6.21 (d, 1H), 4.12 (s, 2H), 3.03 (m, 6H), 2.85 (m, 5H), 2.29 (m, 4H), 2.18 (m,
6H), 1.20 (s,
6H).
EXAMPLE 68
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R4-morpholin-4-ylbut-2-ynyl)oxyl-3-nitrophenyl I sulfony0-2-(1H-pyrrolo [2,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 68A
4-morpholinobut-2-yn-1-ol
To a solution of morpholine (4.36 g) in toluene (15 mL) was added 4-chlorobut-
2-yn-
1-ol (2.09 g) in toluene (5 mL). The solution was stirred at 85 C for 3
hours. After cooling,
the solid was filtered off. The filtrate was subjected to vacuum distillation
to give the pure
title compound.
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EXAMPLE 68B
4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 68A for (tetrahydro-2H-

pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 68C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 4-
R4-morpholin-4-ylbut-2-ynyl)oxyl -3-nitrophenyl}sulfony1)-2-(1H-pyrrolo [2,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 68B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.68 (s,
1H), 8.36 (s, 1H), 8.08 (d, 1H), 8.03 (d, 1H), 7.47-7.53 (m, 4H), 7.35 (d,
2H), 7.04 (d, 2H),
6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 5.15 (s, 2H), 3.52-3.55 (m, 4H),
3.09 (s, 4H), 2.84
(br s, 2H), 2.23-2.40 (m, 6H), 2.12-2.18 (m, 2H), 1.96 (s, 2H), 1.39 (t, 2H),
0.92 (s, 6H).
EXAMPLE 69
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- { [5-
ethyny1-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfonyl}-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 69A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridine-3-
sulfonamide
EXAMPLE 36B (0.176 g), bis(triphenylphosphine)palladium(II) chloride (0.176
g),
copper(I) iodide (0.010 g), N,N-dimethylacetamide (2.5 mL) and triethylamine
(0.105 mL)
were combined, flushed with nitrogen and stirred for 2 minutes.
(Triisopropylsilyl)acetylene
(0.135 mL) was added and the reaction mixture was flushed with nitrogen again,
heated at 60
C overnight, diluted with ethyl acetate, washed with water and brine, dried
(MgSO4),
filtered, concentrated and chromatographed on silica gel with 10-30% ethyl
acetate in
hexanes as the eluent to give the product.
EXAMPLE 69B
5-ethyny1-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
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EXAMPLE 69A (0.205 g) in tetrahydrofuran (3 mL) at ambient temperature was
treated with tetrabutyl ammonium fluoride (1 M in tetrahydrofuran, 0.906 mL)
and stirred at
ambient temperature for 4 hours. Additional tetrabutyl ammonium fluoride (1 M
in
tetrahydrofuran, 1.8 mL) was added and the mixture was heated at 40 C for 45
minutes.
Solid tetrabutyl ammonium fluoride (0.253 g) was added and heating was
continued for 30
minutes. The reaction mixture was concentrated and then chromatographed on
silica gel
using 0-2% methanol in dichloromethane as the eluent to give the product.
EXAMPLE 69
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N- { 115-
ethyny1-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfonyl } -2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 69B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H),
11.41
(s, 1H), 8.58 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.53 (m, 3H), 7.35 (d, 2H),
7.04 (d, 2H),
6.67 (dd, 1H), 6.41 (dd, 1H), 6.18 (d, 1H), 4.56 (s, 1H), 4.24 (d, 2H), 3.87
(dd, 2H), 3.38 (m,
3H), 3.07 (m, 4H), 2.86 (m, 2H), 2.29 (m, 5H), 2.04 (m, 3H), 1.64 (dd, 2H),
1.34 (m, 4H),
0.93 (s, 6H).
EXAMPLE 70
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- 11(4-
oxo-3,4-dihydroquinazolin-6-yl)sulfonyll-2-(1H-pyrrolol2,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 70A
4-amino-3-cyanobenzenesulfonamide
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) was dissolved in dioxane
(4
mL). The solution was cooled to 0 C and 7 mL of an ammonia (7N in methanol)
solution
was added. After the addition was complete, the ice bath was removed and the
reaction was
stirred at room temperature for 24 hours. After concentration of the reaction
mixture, the
crude material was purified by flash chromatography eluting with a gradient of
30-100%
ethyl acetate/hexanes.
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EXAMPLE 70B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-N-(4-amino-3-cyanophenylsulfony1)-4-(4-42-
(4-
chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzamide
The title compound was prepared by substituting EXAMPLE 70A for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G.
EXAMPLE 70C
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-N-(4-amino-3-carbamoylphenylsulfony1)-4-
(4-42-(4-
chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzamide
To a solution of EXAMPLE 70B (90 mg) in ethanol (2 mL) was added
tetrahydrofuran (2 mL), hydrogen peroxide (30%, 1 mL) and 1M sodium hydroxide
solution
(0.48 mL), followed by an additional 2 mL of tetrahydrofuran. The reaction was
heated to
45 C for 30 minutes, cooled, and then quenched with 5% HC1 solution and
extracted twice
with dichloromethane. The extracts were combined and concentrated to obtain
the product.
EXAMPLE 70D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R4-
oxo-3,4-dihydroquinazolin-6-y0sulfonyll-2-(1H-pyrrolol2,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 70C (80 mg) was combined with trimethyl orthoformate (2.3 mL) and
trifluoroacetic acid (0.03 mL) and the resulting solution was stirred at room
temperature for 4
hours. The mixture was purified by flash chromatography, eluting with a
gradient of 3-10%
methanol/dichloromethane. 1H NMR (300MHz, dimethylsulfoxide-d6) 8 12.61 (s,
1H), 11.71
(s, 1H), 8.65 (d, 1H), 8.24 (s, 1H), 8.17 (dd, 1H), 8.04 (m, 1H), 7.73 (d,
1H), 7.57 (d, 1H),
7.51 (m, 2H), 7.39 (d, 2H), 7.07 (d, 2H), 6.70 (dd, 1H), 6.40 (m, 1H), 6.24
(br s, 1H), 3.61
(m, 6H), 3.03 (m, 2H), 2.75 (m, 2H), 2.17 (m, 2H), 2.01 (m, 2H), 1.44 (m, 2H),
0.94 (s, 6H).
EXAMPLE 71
Trans-4-(4- { [8-(4-chlorophenyl)spiro [4.51dec-7-en-7-yll methyl } piperazin-
l-y1)-N-( { 4- l(4-
morpholin-4-ylcyclohexyl)aminol -3 -nitrophenyl } sulfony0-2-(1H-pyrrolo [2,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 71A
8-chlorospirol4.51dec-7-ene-7-carbaldehyde
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To a solution of N,N-dimethylformamide (2.81 mL) in dichloromethane (40 mL)
was
added dropwise POC13 (2.78 mL) at 0 C. The reaction mixture was warmed up to
room
temperature and spirol4.51decan-8-one (3.95 g) in dichloromethane ( 5 mL) was
added
dropwise. The mixture was stirred overnight. The reaction was quenched with
cold aqueous
sodium acetate and the resulting mixture was extracted with ether and the
organic layer was
dried over Na2SO4, filtered, and concentrated to provide the title compound.
EXAMPLE 71B
8-(4-chloropheny0spirol4.51dec-7-ene-7-carbaldehyde
To a suspension of EXAMPLE 71A (3 g) in water (50 mL) was added 4-
chlorophenylboronic acid (2.83 g), tetrabutylammonium (4.87 g), potassium
carbonate (6.26
g) and palladium(II) acetate (0.169 g). The reaction mixture was stirred at 45
C for 5 hours
and extracted with dichloromethane. The organic layer was concentrated and the
residue was
loaded onto a silica gel column, and eluted with 5-20% ethyl acetate in hexane
to give the
title compound.
EXAMPLE 71C
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(8-(4-
chlorophenyl)spiro114.51dec-7-en-7-
yl)uethyl)piperazin-1-y1)benzoate
To a solution of EXAMPLE 71B (274 mg) in dichloroethane (3.5 mL) was added
EXAMPLE 15F (387 mg) and sodium triacetoxyborohydride (317 mg). The reaction
mixture
was stirred overnight. Sodium cyanoborohydride (37.6 mg) was added and the
resulting
mixture stirred overnight. The reaction was quenched with water and diluted
with
dichloromethane. The mixture was washed with water extensively and the organic
layer was
dried over Na2SO4, filtered, and concentrated to provide the title compound.
EXAMPLE 71D
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-48-(4-chlorophenyl)spirol4.51dec-7-
en-7-
y0methyl)piperazin-1-y1)benzoic acid
The title compound was prepared as described in EXAMPLE 3J using EXAMPLE
71C in place of EXAMPLE 31.
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EXAMPLE 71E
Trans-4-(4-{ [8-(4-chlorophenyl)spiro[4.51dec-7-en-7-yllmethyl}piperazin-1-y1)-
N-(14-[(4-
morpholin-4-ylcyclohexyl)amino] -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo 1L2,3 -
b[pyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
71D and EXAMPLE 9C in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (500 MHz, dimethylsulfoxide-d6) 8 11.64 (s, 1H), 8.51 (s, 1H), 8.15 (d,
1H), 8.01 (d,
1H), 7.76 (d, 1H), 7.44 - 7.53 (m, 3H), 7.34 (d, 2H), 7.07 (d, 3H), 6.66 (dd,
1H), 6.37 (dd,
1H), 6.20 (d, 1H), 3.50 - 3.70 (m, 5H), 3.04 (s, 4H), 2.55 - 2.76 (m, 5H),
2.34 - 2.39 (m, 1H),
2.20 (d, 6H), 2.03 (s, 4H), 1.91 (s, 2H), 1.61 (q, 4H), 1.51 (t, 2H), 1.36 -
1.46 (m, 8H).
EXAMPLE 72
Cis-4-(4-{ [4-(4-chloropheny1)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-
yl[methyl}piperazin-1-
y1)-N-[(4- { [(4-methoxycyclohexyl)methyl] amino}-3 -nitrophenyl)sulfonyll -2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
15H and 29A in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H NMR (500
MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.45 (s, 1H), 8.59 (t, 1H), 8.56
(d, 1H), 8.04
(d, 1H), 7.79 (dd, 1H), 7.54 (d, 1H), 7.47 - 7.52 (m, 2H), 7.37 (d, 2H), 7.13
(d, 2H), 7.08 (d,
1H), 6.68 (dd, 1H), 6.35 - 6.42 (m, 1H), 6.19 (d, 1H), 4.11 (s, 2H), 3.37 (s,
1H), 3.26 (t, 2H),
3.20 (s, 3H), 3.07 (s, 4H), 2.83 (s, 2H), 2.17 (d, 6H), 1.81 (dd, 2H), 1.64 -
1.73 (m, 1H), 1.48
(dd, 2H), 1.23 - 1.41 (m, 4H), 1.18 (s, 6H).
EXAMPLE 73
4-(4- { [8-(4-chlorophenyl)spiro[4.51dec-7-en-7-yl[methyl}piperazin-1-y1)-N4 {
4- [(4-
fluorotetrahydro-2H-pyran-4-yl)methoxy] -3 -nitrophenyl}sulfony1)-2-(1H-
pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
71D and EXAMPLE 37D in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (500 MHz, dimethylsulfoxide-d6) 8 11.68 (s, 1H), 8.37 (s, 1H), 7.98 - 8.11
(m, 2H),
4.38 (d, 2H), 3.74 - 3.82 (m, 2H), 3.54 - 3.64 (m, 2H), 3.44 (s, 1H), 3.08 (s,
3H), 2.58 - 2.89
(m, 2H), 2.13 - 2.35 (m, 4H), 2.04 (s, 2H), 1.78 - 1.93 (m, 4H), 1.57 - 1.65
(m, 4H), 1.52 (t,
2H), 1.36 - 1.47 (m, 4H).
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EXAMPLE 74
Trans-4-(4- { 1L8-(4-chlorophenyl)spiro [4.51dec -7-en-7-yll methyl }
piperazin-l-y1)-N- 11(4- { 11(4-
methoxycyclohexyl)methyll amino } -3-nitrophenyl)sulfonyll -2-(1H-pyrrolo
112,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
71D and EXAMPLE 34B in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.39 (s, 1H), 8.58 (t,
1H), 8.56 (d,
1H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.47 - 7.55 (m, 3H), 7.34 (d, 2H), 7.07 (d,
3H), 6.68 (dd,
1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.25 (t, 2H), 3.22 (s, 3H), 3.06 (s, 5H),
2.71 (s, 2H), 2.21 (s,
6H), 1.94 - 2.06 (m, 4H), 1.79 (d, 2H), 1.57 - 1.65 (m, 5H), 1.51 (t, 2H),
1.39 (t, 4H), 0.95 -
1.11 (m, 4H).
EXAMPLE 75
4-(4- { [2-(4-chloropheny1)-5,5-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 75A
methyl 5,5-dimethy1-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
The title compound was prepared by substituting 4,4-dimethy1-2-
methoxycarbonylcyclohexanone for 5,5-dimethy1-2-methoxycarbonylcyclohexanone
in
EXAMPLE 3A.
EXAMPLE 75B
methyl 2-(4-chloropheny1)-5,5-dimethylcyclohex-1-enecarboxylate
The title compound was prepared by substituting EXAMPLE 75A for EXAMPLE 3A
in EXAMPLE 3B.
EXAMPLE 75C
(2-(4-chloropheny1)-5,5-dimethylcyclohex-1-enyl)methanol
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The title compound was prepared by substituting EXAMPLE 75B for EXAMPLE 3B
in EXAMPLE 3C.
EXAMPLE 75D
2-(4-chloropheny1)-5,5-dimethylcyclohex-1-enecarbaldehyde
To a solution of EXAMPLE 75C (2.8 g) in dichloromethane (50 mL) was added
Dess-Martin Periodinane (5.68 g). The reaction mixture was stirred at room
temperature for
3 hours and diluted with ether and washed with 5% NaOH and brine. The organic
layer was
dried over Na2SO4, filtered, and concentrated. The residue was purified by
flash
chromatography using 20% ethyl acetate in hexanes to provide the title
compound.
EXAMPLE 75E
methyl 2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-5,5-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoate
The title compound was prepared by replacing 4'-chlorobipheny1-2-
carboxaldehyde
with EXAMPLE 75D and tert-butyl piperazine-l-carboxylate with EXAMPLE 15F in
EXAMPLE 1A.
EXAMPLE 75F
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-5,5-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
The title compound was prepared as described in EXAMPLE 15H by replacing
EXAMPLE 15G with EXAMPLE 75E.
EXAMPLE 75G
4-(4-112-(4-chloropheny1)-5,5 -dimethylcyclohex-1-en-l-yll methyllpiperazin-1-
y1)-N-(13-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
75F and EXAMPLE 1F in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (400 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.38 (s, 1H), 8.60 (t,
1H), 8.56 (d,
1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.47 - 7.55 (m, 3H), 7.31 - 7.36 (m, 2H),
7.05 - 7.13 (m,
3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.18 (d, 1H), 3.85 (dd, 2H), 3.22 - 3.31
(m, 4H), 3.07 (s,
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4H), 2.67 - 2.78 (m, 2H), 2.19 (s, 6H), 1.82 - 1.98 (m, 3H), 1.56 - 1.66 (m,
2H), 1.39 (t, 2H),
1.17 - 1.33 (m, 3H), 0.93 (s, 6H).
EXAMPLE 76
4-(4-{ 1L2-(4-chloropheny1)-5,5-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [5-
cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yllsulfonyl } -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
75F and EXAMPLE 36C in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (400 MHz, dimethylsulfoxide-d6) 8 11.62 (s, 1H), 8.73 (s, 1H), 8.52 (s,
1H), 7.98 (d,
1H), 7.56 (d, 1H), 7.45 - 7.51 (m, 1H), 7.43 (s, 1H), 7.37 (d, 2H), 7.10 (d,
2H), 6.68 (dd, 1H),
6.35 (dd, 1H), 6.25 (s, 1H), 4.29 (d, 2H), 3.88 (dd, 2H), 3.12 (d, 4H), 2.21
(s, 2H), 2.00 - 2.11
(m, 1H), 1.95 (s, 2H), 1.64 (dd, 2H), 1.27 - 1.46 (m, 4H), 0.95 (s, 6 H)
EXAMPLE 77
tert-butyl 3-{ [4-(1 [4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yll methyl } piperazin-l-y1)-2-(1H-pyrrolo [2,3-blpyridin-5-yloxy)benzoyll
amino I sulfony1)-2-
nitrophenoxylmethyl I morpholine-4-carboxylate
EXAMPLE 77A
tert-butyl 3-((2-nitro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with tert-butyl 3-(hydroxymethyl)morpholine-4-
carboxylate.
EXAMPLE 77B
tert-butyl 3-{ [4-(1 [4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yll methyl } piperazin-l-y1)-2-(1H-pyrrolo [2,3-blpyridin-5-yloxy)benzoyll
amino I sulfony1)-2-
nitrophenoxylmethyl I morpholine-4-carboxylate
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
77A in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.67
(s,
1H), 8.36 (s, 1H), 8.01 - 8.11 (m, 2H), 7.47 - 7.61 (m, 4H), 7.35 (d, 2H),
7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (d, 1H), 6.20 (s, 1H), 4.41 - 4.52 (m, 2H), 4.15 - 4.28 (m,
1H), 3.59 - 3.95 (m,
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3H), 3.51 (d, 1H), 3.34 - 3.43 (m, 1H), 3.10 (s, 5H), 2.84 (s, 2H), 2.28 (s,
4H), 2.15 (s, 2H),
1.96 (s, 2H), 1.20 - 1.45 (m, 12H), 0.92 (s, 6H).
EXAMPLE 78
4-(4-{ 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(morpholin-3 -ylmethoxy)-3 -nitrophenyll sulfonyl } -2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 77B (100 mg) in dichloromethane (10 mL) at 0 C was treated with
trifluoroacetic acid (5 mL) for 20 minutes. The reaction mixture was
concentrated. The
residue was purified by reverse phase HPLC on a C18 column using a gradient of
35-60%
acetonitrile in 0.1% trifluoroacetic acid water to give the title compound as
a trifluoroacetate
salt. The trifluoroacetic acid salt was dissolved in dichloromethane (10 mL)
and washed with
50% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and
concentrated to give the title compound. 1H NMR (400 MHz, dimethylsulfoxide-
d6) 8 11.56
(s, 1H), 8.23 (d, 1H), 7.94 (d, 1H), 7.90 (dd, 1H), 7.57 (d, 1H), 7.42 - 7.46
(m, 1H), 7.31 -
7.37 (m, 3H), 7.25 (d, 1H), 7.01 - 7.09 (m, 2H), 6.64 (dd, 1H), 6.29 - 6.37
(m, 1H), 6.24 (d,
1H), 4.17 - 4.31 (m, 2H), 3.90 - 4.05 (m, 1H), 3.77 - 3.85 (m, 1H), 3.45 -
3.59 (m, 4H), 2.94 -
3.13 (m, 6H), 2.76 (s, 2H), 2.18 (d, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
EXAMPLE 79
4-(4-{ [8-(4-chlorophenyl)spirol4.51dec-7-en-7-yllmethyl}piperazin-1-y1)-N-(13-
nitro-4-
Rtetrahydro-2H-pyran-4-ylmethyBaminolphenyl I sulfony1)-2-(1H-pyrrolo112,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
71D and EXAMPLE 1F in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (400 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.38 (s, 1H), 8.60 (t,
1H), 8.56 (d,
1H), 8.04 (d, 1H), 7.77 - 7.84 (m, 1H), 7.45 - 7.56 (m, 3H), 7.34 (d, 2H),
7.04 - 7.13 (m, 3H),
6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.85 (dd, 2H), 3.22 - 3.31 (m, 4H),
3.07 (s, 4H),
2.71 (s, 2H), 2.21 (s, 6H), 2.03 (s, 2H), 1.81 - 1.94 (m, 1H), 1.56 - 1.68 (m,
6H), 1.51 (t, 2H),
1.34 - 1.45 (m, 4H), 1.20 - 1.33 (m, 2H).
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EXAMPLE 80
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f [1-(methylsulfonyl)piperidin-4-yll amino I -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting 1-(methylsulfonyl)piperidin-4-
amine
for 1-acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz,
dimethylsulfoxide-d6)
8 11.67 (br s, 1H), 8.57 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H),
7.54-7.46 (m, 3H),
7.35 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.20
(d, 1H), 3.80 (m,
1H), 3.57 (m, 2H), 3.08 (br s, 4H), 2.95 (td, 2H), 2.92 (s, 3H), 2.85-2.72 (m,
2H), 2.30-2.10
(m, 6H), 2.07-1.93 (m, 4H), 1.70 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 81
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R1,1-dioxidotetrahydro-2H-thiopyran-4-y1)aminol-3-nitrophenyl I sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 81A
1,1-Dioxotetrahydro-2H-thiopyran-4-amine
N-Benzy1-1,1-dioxotetrahydro-2H-thiopyran-4-amine (2.00 g) was added to
ethanol
(40 mL) in a pressure bottle. Palladium hydroxide on carbon (0.587 g,) was
added and the
solution was stirred under 30 psi of hydrogen at room temperature for 2 hours.
The mixture
was filtered though a nylon membrane and the solvent was removed under vacuum.
EXAMPLE 81B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R1,1-dioxidotetrahydro-2H-thiopyran-4-y1)aminol-3-nitrophenyl I sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 81A for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz, dimethylsulfoxide-d6)
8
11.65 (br s, 1H), 8.55 (d, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.86 (dd, 1H),
7.52-7.47 (m, 3H),
7.35 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.21
(d, 1H), 4.05 (m,
1H), 3.22-3.00 (m, 8H), 2.79 (br s, 2H), 2.31-2.11 (m, 10H), 1.96 (br s, 2H),
1.39 (t, 2H),
0.93 (s, 6H).
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EXAMPLE 82
N- [(4-chloro-3-nitrophenyl)sulfony11-4-(4- { 1L2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-en-
1-yllmethyl}piperazin-1-y1)-2-(1H-pyrrolo [2,3 -b[pyridin-5 -yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G. 1H NMR
(300MHz, dimethylsulfoxide-d6) 8 11.60 (br s, 1H), 8.38 (br s, 1H), 7.96 (d,
1H), 7.91 (d,
1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.46 (t, 1H), 7.39-7.35 (m, 3H), 7.07 (d,
2H), 6.67 (dd, 1H),
6.34 (m, 1H), 6.28 (d, 1H), 3.31 (br s, 2H), 3.17 (br s, 8H), 2.18 (m, 2H),
1.98 (br s, 2H), 1.42
(t, 2H), 0.94 (s, 6H).
EXAMPLE 83
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(3 -
nitro-4- { [1-(2,2,2-trifluoroethyl)piperidin-4-yl] amino}phenyl)sulfony11-2-
(1H-pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
EXAMPLE 83A
3-Nitro-4-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylaminol-benzenesulfonamide
The title compound was prepared by substituting 1-(2,2,2-
trifluoroethyl)piperidin-4-
amine hydrochloride for (tetrahydropyran-4-yl)methylamine in EXAMPLE 6A.
EXAMPLE 83B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(3 -
nitro-4- { [1-(2,2,2-trifluoroethyl)piperidin-4-yll amino}phenyl)sulfony11-2-
(1H-pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 82A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.66 (br s, 1H), 8.56 (d, 1H), 8.24 (d, 1H), 8.04 (d,
1H), 7.81 (dd,
1H), 7.52 (dd, 2H), 7.48 (d, 1H), 7.35 (d, 2H), 7.15 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H), 6.38
(m, 1H), 6.20 (d, 1H), 3.68 (m, 1H), 3.22 (q, 2H), 3.07 (br s, 4H), 2.90 (m,
2H), 2.75 (br s,
2H), 2.29-2.12 (m, 8H), 1.97-1.86 (m, 4H), 1.63 (m, 2H), 1.38 (t, 2H), 0.92
(s, 6H).
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EXAMPLE 84
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 5-
cyano-6-R1-tetrahydro-2H-pyran-4-ylpiperidin-4-yBoxylpyridin-3-yl}sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 84A
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol
Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) were dissolved
in
titanium(IV) isopropoxide (30 mL) and the reaction was stirred at room
temperature
overnight. Methanol (40 mL) was added and the reaction was cooled to 0 C. Then
NaBH4
(3.8 g) was added in portions over one hour. After 2 hours 1N aqueous NaOH was
added,
followed by ethyl acetate addition. After filtration though celite the layers
were separated, the
aqueous layer extracted with ethyl acetate, and the combined organic layers
were dried over
Na2SO4. The crude was purified by column chromatography using dichloromethane
having 5-
10% 7N NH3 in methanol.
EXAMPLE 84B
5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 84A for (tetrahydro-2H-

pyran-4-yl)methanol and EXAMPLE 36A for 4-fluoro-3-nitrobenzenesulfonamide in
EXAMPLE 24A.
EXAMPLE 84C
5-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 84D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 5-
c yano-6- R1-tetrahydro-2H-pyran-4-ylpiperidin-4-yBoxylpyridin-3-yl}sulfony1)-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 84C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.50 (s, 1H),
8.60 (d,
1H), 8.37 (d, 1H), 7.90 (d, 1H), 7.60 (d, 1H), 7.42 (dd, 1H), 7.35 (d, 2H),
7.25 (d, 1H), 7.04
(d, 2H), 6.63 (dd, 1H), 6.28 (m, 1H), 6.24 (d, 1H), 5.30 (br s, 1H), 4.50 (d,
2H), 3.95 (dd,
2H), 3.30 (m, 5H), 3.02 (br s, 4H), 2.95 (br s, 2H), 2.24 (br s, 4H), 2.17 (br
m, 4H), 1.96 (s,
2H), 1.90 (br m, 4H), 1.60 (br m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 85
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en- 1-yll methyllpiperazin-
1-y1)-N-115 -
is opropy1-6- (tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfony11-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 85A
5 -is opropy1-6-((tetrahydro-2H-pyran-4- yl)methoxy)pyridine-3- sulfonamide
EXAMPLE 36B (0.176 g), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.041
g), and palladium(II) acetate (0.011 g) were combined in a 10 mL oven-dried
flask.
Tetrahydrofuran (1 mL) was added and the mixture was flushed with nitrogen and
stirred at
ambient temperature for 5 minutes. 2-Propylzinc bromide solution (0.5 M in
tetrahydrofuran)
(1.5 mL) was added and stirring was continued under nitrogen overnight.
Additional 2-2-
dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.041 g) and palladium(II)
acetate (0.011 g)
were added. The mixture was flushed with nitrogen and stirred at ambient
temperature for 5
minutes. 2- Propylzinc bromide solution (0.5 M in tetrahydrofuran) (1.5 mL)
was added and
stirring was continued under nitrogen for 2.5 days. The reaction mixture was
diluted with
ethyl acetate, washed with water and brine, dried (MgSO4), filtered,
concentrated, and
chromatographed on silica gel with 0 to 3% methanol in CH2C12 as the eluent.
The obtained
material was chromatographed on silica gel a second time with 10-40% ethyl
acetate in
CH2C12 as the eluent, triturated with diethyl ether and dried under vacuum at
45 C to give the
product.
EXAMPLE 85B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en- 1-yll methyllpiperazin-
1-y1)-N-115 -
is opropy1-6- (tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfony11-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 85A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.70 (s, 1H),
8.49
(m, 1H), 8.04 (d, 1H), 7.90 (m, 1H), 7.57 (m, 1H), 7.52 (t, 1H), 7.48 (dd,
1H), 7.34 (d, 2H),
7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd, 1H), 6.17 (s, 1H), 4.19 (m, 2H), 3.88
(m, 2H), 3.30 (m,
2H), 3.05 (m, 5H), 2.77 (s, 2H), 2.21 (s, 4H), 2.14 (s, 2H), 2.03 (m, 1H),
1.95 (s, 2H), 1.64
(m, 2H), 1.34 (m, 4H), 1.12 (d, 6H), 0.92 (s, 6H).
EXAMPLE 86
N-(13 -chloro-5-fluoro-4- Rtetrahydro-2H-pyran-4-
ylmethyl)aminolphenyllsulfony1)-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 86A
3-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting 3,4-difluorobenzenesulfonamide
for
4-chloro-3-nitrobenzenesulfonamide and (tetrahydro-2H-pyran-4-yl)methanamine
for 4-
methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 86B
3-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE
52B in EXAMPLE 52C.
EXAMPLE 86C
N-(13 -chloro-5-fluoro-4- Rtetrahydro-2H-pyran-4-
ylmethyBaminolphenyllsulfony1)-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.72 (s, 1H),
11.20
(s, 1H), 8.08 (d, 1H), 7.61 (m, 2H), 7.50 (m, 3H), 7.34 (d, 2H), 7.04 (d, 2H),
6.68 (dd, 1H),
6.42 (dd, 1H), 6.16 (d, 1H), 6.09 (m, 1H), 3.81 (dd, 2H), 3.25 (m, 4H), 3.07
(m, 4H), 2.76 (s,
2H), 2.18 (m, 6H), 1.95 (s, 2H), 1.72 (m, 1H), 1.53 (d, 2H), 1.38 (t, 2H),
1.16 (m, 2H), 0.92
(s, 6H).
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EXAMPLE 87
4-14- R4'-chloro-1,1'-bipheny1-2-yl)methyllpiperazin-l-y11-2-(1H-indo1-5-
yloxy)-N-(13 -
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfonyl) benzamide
EXAMPLE 87A
methyl 2-(1H-indo1-5-yloxy)-4-fluorobenzoate
The title compound was prepared by substituting 5-hydroxyindole for
EXAMPLE 3G in EXAMPLE 3H.
EXAMPLE 87B
methyl 2-(1H-indo1-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoate
The title compound was prepared by substituting EXAMPLE 87A for
EXAMPLE 3H in EXAMPLE 31.
EXAMPLE 87C
2-(1H-indo1-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 87B for EXAMPLE 31
in EXAMPLE 3J.
EXAMPLE 87D
4-14- R4'-chloro-1,1'-bipheny1-2-yl)methyllpiperazin-1-y11-2-(1H-indo1-5-
yloxy)-N-(13-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE 1E
in EXAMPLE 1G, except here the crude was purified by preparative HPLC using a
250 x 50
mm C18 column and eluting with 20-100% CH3CN vs. 0.1% trifluoroacetic acid in
water,
giving the product as a trifluoroacetate salt. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8
11.40 (br s, 1H), 11.17 (s, 1H), 9.50 (v br s, 1H), 8.61 (t, 1H), 8.57 (d,
1H), 7.77 (dd, 1H),
7.70 (br s, 1H), 7.50 (m, 5H), 7.36 (m, 5H), 7.10 (s, 1H), 7.08 (d, 1H), 6.83
(dd, 1H), 6.69
(dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.30 (br s, 1H), 3.84 (dd, 2H), 3.70 (br
s, 1H), 3.30 (m,
6H), 3.20, 2.95, 2.80 (all br s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25
(m, 2H).
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EXAMPLE 88
4- { 4- R4'-chloro-1,1'-bipheny1-2-yl)methyllpiperazin-l-yl } -2-(1H-indo1-5-
yloxy)-N-( { 4- R3-
morpholin-4-ylpropyl)aminol -3-nitrophenyl } sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE 1E
and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G, except here the crude was
purified
by preparative HPLC using a 250 x 50 mm C18 column and eluting with 20-100%
CH3CN
vs. 0.1% trifluoroacetic acid in water, giving the product as a
trifluoroacetate salt. 1H NMR
(300 MHz, dimethylsulfoxide-d6) 8 11.40 (br s, 1H), 11.19 (s, 1H), 9.60 (v br
s, 1H), 8.69 (t,
1H), 8.60 (d, 1H), 7.83 (dd, 1H), 7.65 (br s, 1H), 7.50 (m, 5H), 7.38 (m, 5H),
7.12 (m, 2H),
6.83 (dd, 1H), 6.69 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 4.38 (br s, 1H),
4.00 (m, 2H), 3.80
(br s, 1H), 3.40 (m, 4H), 3.30-2.80 (envelope, 10H), 3.20 (m, 4H), 1.96 (m,
2H).
EXAMPLE 89
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
indo1-5-yloxy)-N-(13-nitro-4-R1-tetrahydro-2H-pyran-4-ylpiperidin-4-
yl)aminolphenyl I sulfonyl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 87C for EXAMPLE 1E
and EXAMPLE 3M for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.15 (s, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.84 (dd,
1H), 7.52 (d, 1H),
7.39 ¨ 7.31 (m, 4H), 7.12 (d, 2H), 7.04 (d, 2H), 6.84 (dd, 1H), 6.65 (dd, 1H),
6.38 (t, 1H),
6.14 (d, 1H), 3.94 (m, 2H), 3.84 (m, 1H), 3.02 (m, 8H), 2.79 (m, 3H), 2.72 (s,
2H), 2.20-2.02
(m, 8H), 1.85 (m, 6H), 1.60 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 90
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
indol-5-yloxy)-N-(1 4- R1-methylpiperidin-4-yl)aminol-3-nitrophenyl I
sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE 1E
and EXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.08 (s, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.78 (dd,
1H), 7.52 (d, 1H),
7.37 ¨ 7.31 (m, 4H), 7.06 - 7.00 (m, 4H), 6.79 (dd, 1H), 6.59 (dd, 1H), 6.35
(t, 1H), 6.14 (d,
1H), 3.73 (m, 1H), 3.05 - 2.95 (m, 6H), 2.71 (s, 2H), 2.60 (m, 2H), 2.48 (s,
3H), 2.16 (m, 6H),
2.01 (m, 2H), 1.95 (s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
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EXAMPLE 91
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
indo1-5-yloxy)-N-( { 4- R4-methylpiperazin-1-yl)aminol-3-nitrophenyl }
sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE 11B
and EXAMPLE 87C for EXAMPLE 3J in EXAMPLE 11D. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 6 11.14 (s, 1H), 9.18 (s, 1H), 8.53 (d, 1H), 7.84 (dd,
1H), 7.56 (d, 1H),
7.51 (d, 1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.12 (d, 1H), 7.03 (d, 2H), 6.84
(dd, 1H), 6.62 (dd,
1H), 6.38 (m, 1H), 6.13 (d, 1H), 3.00 (m, 4H), 2.90 (m, 4H), 2.71 (s, 2H),
2.33 (s, 3H), 2.15
(m, 6H), 1.94 (s, 2H), 1.37 (t, 2H), 0.92 (s, 6H).
EXAMPLE 92
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(1,4-dioxan-2-ylmethoxy)-3 -nitrophenyll sulfonyl } -2-(1H-indo1-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
87C and EXAMPLE 12A in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (500 MHz, dimethylsulfoxide-d6) 8 11.16 (s, 2H), 8.39 (d, 1H), 8.06 (dd,
1H), 7.51 (d,
1H), 7.38 - 7.43 (m, 3H), 7.34 (d, 2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd,
1H), 6.64 (dd,
1H), 6.39 (s, 1H), 6.15 (d, 1H), 4.20 - 4.28 (m, 2H), 3.85 - 3.91 (m, 1H),
3.82 (dd, 1H), 3.74 -
3.78 (m, 1H), 3.59 - 3.69 (m, 2H), 3.40 - 3.51 (m, 2H), 3.05 (s, 4H), 2.78 (s,
2H), 2.23 (s,
4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 93
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
indol-5-yloxy)-N4 { 4- R2-methoxyethyl)aminol-3-
Rtrifluoromethyl)sulfonyllphenyl I sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE 3J
and EXAMPLE 16A for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (400MHz,
dimethylsulfoxide-d6) 8 11.17 (s, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.49 (d,
1H), 7.40 (m,
2H), 7.33 (d, 2H), 7.26 (m, 1H), 7.17 (d, 1H), 7.04 (m, 3H), 6.86 (dd, 1H),
6.65 (dd, 1H),
6.40 (s, 1H), 6.14 (d, 1H), 3.51 (m, 4H), 3.28 (s, 3H), 3.03 (s, 4H), 2.74 (s,
2H), 2.16 (m, 6H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
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EXAMPLE 94
4-(4- { [2-(4-chloropheny0-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
indol-5-yloxy)-N-( { 4-Rtetrahydro-2H-pyran-4-ylmethyl)amino[-3-
Rtrifluoromethyl)sulfonyllphenyllsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE 3J
and EXAMPLE 17A for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (400MHz,
dimethylsulfoxide-d6) 8 11.20 (s, 1H), 8.19 (d, 1H), 7.90 (dd, 1H), 7.53 (d,
1H), 7.40 (m,
4H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (m, 3H), 6.86 (dd, 1H), 6.70 (dd, 1H),
6.41 (s, 1H), 6.21
(d, 1H), 3.84 (dd, 2H), 3.59 (m, 2H), 3.25 (m, 6H), 3.00 (m, 2H), 2.74 (s,
2H), 2.54 (m, 2H),
2.18 (s, 2H), 2.01 (s, 2H), 1.83 (m, 1H), 1.54 (m, 2H), 1.45 (t, 2H), 1.23 (m,
2H), 0.94 (s,
6H).
EXAMPLE 95
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 1- [2-fluoro-1-(fluoromethyBethyllpiperidin-4-yl}amino)-3-nitrophenyfl
sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 95A
1-(1,3-difluoropropan-2-yl)piperidin-4-amine
Tert-butyl piperidin-4-ylcarbamate (0.212 g), 1,3-difluoropropan-2-one (0.149
g) and
sodium triacetoxyborohydride (0.337 g) were stirred together in dichloroethane
at room
temperature. After stirring overnight the reaction was quenched with water (10
mL) and
extracted into dichloromethane (2 x 20 mL). The organic layer was dried over
magnesium
sulfate, filtered, and concentrated. The residue was treated with hydrogen
chloride (4.0M in
dioxane, 1.323 ml) for 1 hour to give the title compound as the HC1 salt after
concentration.
EXAMPLE 95B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yl[methyl}piperazin-1-
y1)-N- { [4-
({ 1- [2-fluoro-1-(fluoromethyBethyl[piperidin-4-yl}amino)-3-
nitrophenyllsulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 95A (0.057 g) and EXAMPLE 53A (0.162 g) were suspended in dioxane
(3 mL) and heated to 105 C overnight. The reaction was concentrated, loaded
onto silica gel
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(GraceResolv 12 g) and eluted with a gradient of 0.5% to 4%
methanol/dichloromethane.
The product containing fractions were concentrated and loaded onto C18 (SF25-
75g analogix
column) and eluted using a gradient of 30% to 60% acetonitrile/water. The
product was
partitioned between dichloromethane (20 mL) and saturated aqueous NaHCO3
solution (20
mL). The organic layer was dried over magnesium sulfate, filtered, and
concentrated to give
the title compound. 1H NMR (300 MHz, CDC13) 6 10.10 (s, 1H), 8.88 (d, 2H),
8.45 (d, 1H),
8.20 (s, 1H), 8.18 - 8.09 (m, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 7.44 (s, 1H),
7.23 - 7.19 (m, 1H),
6.91 (d, 3H), 6.53 (d, 2H), 5.98 (d, 1H), 4.64 (dd, 4H), 3.68 - 3.50 (m, 1H),
3.01 (d, 6H), 2.72
(d, 4H), 2.19 (s, 11H), 1.69 (s, 2H), 1.41 (s, 2H), 0.94 (s, 6H).
EXAMPLE 96
N-(15-chloro-6-R4-fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-
yllsulfony1)-4-(4-
1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-yllmethyllpiperazin-l-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 96A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide and EXAMPLE 37C for (tetrahydro-2H-pyran-4-yl)methanol
in
EXAMPLE 24A.
EXAMPLE 96B
N-(15-chloro-6- R4-fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-
yllsulfony1)-4-(4-
1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 96A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.52 (s,
1H), 8.41 (s, 1H), 8.03 (d, 1H), 7.56 (d, 1H), 7.50 (m, 2H), 7.35 (d, 2H),
7.04 (d, 2H), 6.67
(dd, 1H), 6.39 (m, 1H), 6.22 (s, 1H), 4.50 (d, 2H), 3.78 (m, 2H), 3.60 (m,
2H), 3.12 (v br s,
4H), 2.93 (v br s, 2H), 2.38 (v br s, 4H), 2.17 (br m, 2H), 1.96 (s, 2H), 1.86
(m, 4H), 1.40 (t,
2H), 0.93 (s, 6H).
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EXAMPLE 97
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ 111-(2,2-difluoroethyl)piperidin-4-yll amino } -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 97A
tert-butyl 4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate
The title compound was prepared by substituting tert-butyl 4-aminopiperidine-1-

carboxylate for 4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 97B
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide
Tert-butyl 4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate was
dissolved in dichloromethane (3 mL) and treated with 1N HC1 in ether (4 mL).
The reaction
was stirred overnight then concentrated to give the title compound.
EXAMPLE 97C
4-(1-(2,2-difluoroethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.100g ), 1,1-

difluoro-2-iodoethane (0.063 mL) and diisopropylamine (0.156 mL) were stirred
together in
N,N-dimethylformamide (3 ml) and heated to 85 C. The reaction was diluted with

dichloromethane (50 mL) and washed with water (50 mL), brine (50 mL), dried
over
magnesium sulfate, filtered, and concentrated. The residue was loaded onto
silica gel
(GraceResolve 12g) and eluted using a gradient of 0.5%
methanol/dichloromethane to 3%
methanol/dichloromethane over 30 minutes to give the title compound.
EXAMPLE 97D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- 11(4-
{ 111-(2,2-difluoroethyl)piperidin-4-yll amino } -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 97B for EXAMPLE 1F
and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.67 (s, 1H), 11.54 - 11.27 (m, 1H), 8.55 (d, 1H),
8.24 (d, 1H), 8.03
(d, 1H), 7.81 (d, 1H), 7.50 (dd, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04 (d,
2H), 6.68 (d, 1H),
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6.38 (dd, 1H), 6.15 (dt, 2H), 3.64 (s, 1H), 3.07 (s, 4H), 2.79 (ddd, 6H), 2.41
(t, 2H), 2.17 (d,
6H), 1.92 (d, 4H), 1.61 (d, 2H), 1.38 (s, 2H), 0.92 (s, 6H).
EXAMPLE 98
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-({4-
R1-cyclopropylpiperidin-4-yl)aminol -3-nitrophenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 53B by replacing 1-
acetylpiperidin-4-amine with 4-amino-1-cyclopropylpiperidine. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.65 (s, 1H), 8.54 (d, 1H), 8.22 (d, 1H), 8.02 (d,
1H), 7.80 (dd, 1H),
7.49 (m, 3H), 7.34 (d, 2H), 7.11 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38
(dd, 1H), 6.19 (d,
1H), 3.69 (m, 1H), 3.06 (m, 4H), 2.92 (m, 2H), 2.74 (s, 2H), 2.23 (m, 7H),
1.93 (m, 5H), 1.77
(m, 1H), 1.55 (m, 3H), 1.38 (t, 2H), 0.92 (s, 6H), 0.43 (m, 4H).
EXAMPLE 99
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R4-
{ R1-morpholin-4-ylcyclohexyl)methyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 53B by replacing 1-
acetylpiperidin-4-amine with 1-(4-morpholino)cyclohexanemethylamine. 1H NMR
(300
MHz, dimethylsulfoxide-d6) 8 11.70 (s, 1H), 9.06 (s, 1H), 8.59 (d, 1H), 8.06
(d, 1H), 7.83
(dd, 1H), 7.57 (d, 1H), 7.50 (m, 2H), 7.34 (m, 3H), 7.19 (d, 1H), 7.04 (d,
2H), 6.67 (dd, 1H),
6.41 (dd, 1H), 6.17 (d, 1H), 3.56 (m, 6H), 3.44 (m, 2H), 3.07 (m, 5H), 2.57
(m, 5H), 2.24 (m,
6H), 1.95 (s, 3H), 1.45 (m, 6H), 1.23 (m, 3H), 0.92 (s, 6H).
EXAMPLE 100
Trans-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }
piperazin-1-y1)-N-
R4- { [4-(dicyclopropylamino)cyclohexyllamino } -3-nitrophenyl)sulfony11-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 100A
Trans-tert-butyl-4-(dicyclopropylamino)cyclohexylcarbamate
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A suspension of trans-tert-butyl-4-aminocyclohexylcarbamate (1 g), molecular
sieves
3A (1 g), acetic acid (2.67 ml), (1-ethoxycyclopropoxy)trimethysilane (3.74
ml) and sodium
cyanoborohydride (0.880 g) in dry methanol (10 ml) was heated at reflux for 3
hours. The
insolubles were filtered off, the resulting solution was basified with aqueous
NaOH (6 M) to
pH 14, and extracted with ether. The combined extracts were washed with brine,
dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography (silica
gel 80 g, 30 - 100% acetone/hexanes) to provide the title compound.
EXAMPLE 100B
(trans)-N1,N1-dicyclopropylcyclohexane-1,4-diamine bis(2,2,2-trifluoroacetate)
The title compound was prepared by substituting EXAMPLE 100A for EXAMPLE
39A in EXAMPLE 39B.
EXAMPLE 100C
Trans-4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-y1)-N-
1(4-114-(dicyclopropylamino)cyclohexyll amino1-3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
A suspension of EXAMPLE 53A (0.14 g), EXAMPLE 100B (0.112 g) and N,N-
diisopropylethylamine (0.310 mL) in dioxane (10 mL) was stirred for 3 days at
100 C. The
20product was concentrated and purified by RP HPLC(C8, 30% - 100%
CH3CN/water/0.1%
trifluoroacetic acid). 1H NMR (500 MHz, pyridine-d5) 8 13.07 (s, 1H), 9.28 (d,
1H), 8.41 - 8.45
(m, 2H), 8.37 (d, 1H), 8.12 (d, 1H), 7.67 (d, 2H), 7.44 (d, 2H), 7.07 (d, 2H),
7.01 (d, 1H), 6.75
(dd, 1H), 6.53 (d, 1H), 6.48 - 6.51 (m, 1H), 3.43 (ddd, 1H), 3.03 - 3.09 (m,
4H), 2.72 - 2.79 (m,
3H), 2.22 - 2.28 (m, 2H), 2.11 - 2.16 (m, 4H), 2.10 (s, 2H), 2.00 - 2.05 (m,
2H), 1.97 (s, 2H), 1.89
25(s, 1H), 1.86 (s, 3H), 1.62 - 1.71 (m, 2H), 1.39 (t, 2H), 1.19 - 1.29 (m,
2H), 0.93 (s, 6H), 0.48 (d,
8H).
EXAMPLE 101
4-(4-112-(4-chloropheny1)-6,6-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
30 nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
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EXAMPLE 101A
Ethyl 2-hydroxy-6,6-dimethylcyclohex-1-enecarboxylate
Into a 500 mL flame dried round-bottomed flask was added copper(I) iodide (18
g) in
ether (200 mL) to give a suspension. After cooling to -5 C, methyllithium (120
mL, 1.6M in
ether) was added dropwise. After stirring at -5 C for 1 hour, 3-methylcyclohex-
2-enone (5.15
mL) in 15 ml ether was added dropwise, and the mixture was stirred at -5 C for
1 hour. After
cooling to ¨78 C, hexamethylphosphoramide (60 mL) was added dropwise. Ethyl
carbonocyanidate (23.74 mL) was added. After stirring at -78 C for 20
minutes, the mixture
was warmed up to room temperature, and stirred for 1 hour. The mixture was
poured into
cold water, and the layers were separated. The aqueous layer was extracted
with ether (3x 20
mL). The combined organic layers were washed with saturated aqueous NH4C1 (3x
20 mL),
dried over Na2SO4, filtered, and dried under vacuum. The crude product was
added to a silica
gel column and purified by eluting with 0-10% ethyl acetate in hexane.
EXAMPLE 101B
Ethyl 6,6-dimethy1-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
Into a 500 mL round-bottomed flask was added hexane-washed sodium hydride (0.5

g) in dichloromethane (100 mL) to give a suspension. After cooling to -5 C,
EXAMPLE
101A (2.0 g) was added. After stirring at -5 C for 30 minutes, the mixture
was cooled to -
78 C. Trifluoromethanesulfonic anhydride (2.2 mL) was added. The mixture was
warmed to
room temperature and stirred overnight. Water was added slowly to the mixture,
the aqueous
layer was then extracted by dichloromethane (2x 20 mL). The combined organic
layers were
washed with saturated NH4C1 and brine, dried over Na2SO4, filtered, and
concentrated.
EXAMPLE 101C
ethyl 2-(4-chloropheny0-6,6-dimethylcyclohex-1-enecarboxylate
Into a 25 mL microwave tube was added EXAMPLE 101B (2.9 g), 4-
chlorophenylboronic acid (2.2 g), and tetrakis(triphenylphosphine)palladium
(0.05 g) in 1,2-
dimethoxyethane/methanol(2:1, 10 mL) to give a solution. Cesium fluoride (4 g)
was then
added. The reaction mixture was stirred at 150 C under (100W) in a Biotage
Initiator
microwave reactor for 30 minutes. After removing the solvents, water was
added, and the
mixture was extracted with ethyl acetate (2x). The combined organic layers
were dried by
MgSO4. After filtering, the crude product was purified by reverse phase
chromatography
eluting with 50-100% acetonitrile/water with 0.1% trifluoroacetic acid.
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EXAMPLE 101D
(2-(4-chloropheny1)-6,6-dimethylcyclohex-1-enyl)methanol
In a 100 mL round-bottomed flask was placed lithium aluminum hydride (1 g) in
ether (20 mL) to give a suspension. EXAMPLE 101C (1 g) dissolved in ether (5
mL) was
added slowly by syringe. The mixture was stirred at room temperature
overnight. After
cooling to 0 C, the reaction was quenched by water. Ether (2x 10 mL) was used
to extract the
product. The crude product was purified by flash chromatography on silica by
eluting with 0-
15% ethyl acetate in hexane.
EXAMPLE 101E
Methyl 2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-6,6-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoate
To a 0 C solution of EXAMPLE 101D (0.43 g) in dichloromethane (5 mL) was added

triethylamine (1 mL). Methanesulfonyl chloride (0.134 mL) was then added
slowly. After 5
minutes, EXAMPLE 15F (0.61 g) was added. The mixture was stirred at room
temperature
overnight. The crude product was purified by flash chromatography on silica
with 0 to 25%
ethyl acetate in hexanes to provide the title compound.
EXAMPLE 101F
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-6,6-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoic acid
In a 5 mL microwave tube was added lithium hydroxide hydrate (15 mg) and
EXAMPLE 101E (45 mg) in dioxane/water(2:1) (2 mL) to give a suspension. The
mixture
was heated to 130 C in a Biotage Initiator microwave reactor for 20 minutes.
After cooling
and neutralization by HC1, the crude product was added to a Prep HPLC column
and was
eluted with 20-80% acetonitrile/water with 0.1% trifluoroacetic acid.
EXAMPLE 101G
4-(4-112-(4-chloropheny1)-6,6-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(13-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 101F for EXAMPLE 3J
and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 6 11.68 (s, 1H), 11.47 (s, 1H), 8.58 (m, 2H), 8.03 (m,
1H), 7.79 (m,
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1H), 7.51 (m, 3H), 7.31 (d, 2H), 7.10 (m, 1H), 7.02 (d, 2H), 6.65 (m, 1H),
6.39 (m, 1H), 6.15
(m, 1H), 3.85 (m, 2H), 3.27 (m, 4H), 2.97 (m, 4H), 2.76 (s, 2H), 2.14 (m, 6H),
1.70 (m, 2H),
1.61 (m, 2H), 1.44 (m, 2H), 1.26 (m, 3H), 1.16 (m, 6H)
EXAMPLE 102
N-(15-bromo-6-1(4-ethylmorpholin-3-yl)methoxylpyridin-3-yllsulfony1)-4-(4-112-
(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-l-yllmethyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 102A
(4-ethylmorpholin-3-yl)methanol
Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in N,N-
dimethylformamide was treated with K2CO3 (1.1 g) overnight. The reaction
mixture was
diluted with water and extracted with ethyl acetate. The organic layer was
dried over
Na2SO4, filtered, and concentrated to provide the title compound.
EXAMPLE 102B
5-bromo-6-((4-ethylmorpholin-3-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared as described in EXAMPLE 12A by replacing 4-
fluoro-3-nitrobenzenesulfonamide and (1,4-dioxan-2-yl)methanol with 5-bromo-6-
fluoropyridine-3-sulfonamide and EXAMPLE 102A, respectively.
EXAMPLE 102C
N-(15-bromo-6-1(4-ethylmorpholin-3-yl)methoxylpyridin-3-yllsulfony1)-4-(4-112-
(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
102B in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.62
(s,
1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H), 7.45 - 7.50 (m,
2H), 7.35 (d, 2H),
7.05 (d, 2H), 6.66 (dd, 1H), 6.37 (s, 1H), 6.21 (d, 1H), 4.58 (dd, 1H), 4.39 -
4.50 (m, 1H),
3.78 - 3.90 (m, 1H), 3.67 - 3.77 (m, 1H), 3.50 - 3.65 (m, 2H), 3.08 (s, 4H),
2.59 - 3.00 (m,
4H), 2.20 - 2.39 (m, 2H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.99 -
1.11 (m, 3H), 0.93 (s,
6H)
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EXAMPLE 103
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 4-
R4-ethylmorpholin-3 -yl)methoxyl -3-nitrophenyl}sulfony1)-2-(1H-pyrrolo [2,3-
bl pyridin-5-
yloxy)benzamide
EXAMPLE 103A
4-((4-ethylmorpholin-3-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with EXAMPLE 102A.
EXAMPLE 103B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 4-
R4-ethylmorpholin-3 -yl)methoxyl -3-nitrophenyl}sulfony1)-2-(1H-pyrrolo [2,3-
bl pyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
103A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.66
(s,
1H), 8.33 (s, 1H), 7.99 - 8.06 (m, 2H), 7.47 - 7.57 (m, 3H), 7.45 (d, 1H),
7.35 (d, 2H), 7.04
(d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.42 (dd, 1H), 4.23 (dd,
1H), 3.81 (d, 1H),
3.69 (d, 1H), 3.49 - 3.63 (m, 2H), 3.08 (s, 4H), 2.92 (s, 1H), 2.81 (s, 4H),
2.54 (s, 1H), 2.25
(s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 1.00 (t, 3H), 0.92 (s, 6H)
EXAMPLE 104
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 3-
nitro-4- R4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxylphenyl}sulfony1)-2-
(1H-
pyrrolo [2,3 -bl pyridin-5- yloxy)benzamide
EXAMPLE 78 (20 mg) and dihydro-2H-pyran-4(3H)-one (10 mg) in dichloroethane
(2 mL) was treated with NaCNBH3 (9.74 mg) overnight. Additional dihydro-2H-
pyran-
4(3H)-one (20 mg) and titanium (IV) isoproxide (0.05 mL) were added. The
resulting
mixture was stirred at room temperature overnight and concentrated. The
residue was
purified by reverse phase HPLC on a C18 column using a gradient of 35-60%
acetonitrile in
0.1% trifluoroacetic acid water to give the title compound as a
trifluoroacetate salt. The
trifluoroacetic acid salt was dissolved in dichloromethane (6 mL) and washed
with 50%
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aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and
concentrated to
give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.68 (s,
1H), 8.35 (s,
1H), 8.04 (s, 2H), 7.44 - 7.58 (m, 4H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd,
1H), 6.40 (s, 1H),
6.20 (s, 1H), 4.44 (s, 1H), 4.28 (s, 1H), 3.85 (d, 2H), 3.71 (d, 1H), 3.61 (s,
3H), 3.20 - 3.29
(m, 2H), 3.08 (s, 5H), 2.54 - 2.96 (m, 5H), 2.06 - 2.42 (m, 5H), 1.96 (s, 2H),
1.77 (d, 1H),
1.53 - 1.66 (m, 1H), 1.29 - 1.51 (m, 4H), 0.92 (s, 6H)
EXAMPLE 105
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3-
nitro-4- { R3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 105A
(S)-tert-butyl 1-(tetrahydro-2H-pyran-4-yl)piperidin-3-ylcarbamate
The title compound was prepared by substituting (S)-tert-butyl piperidin-3-
ylcarbamate for tert-butyl piperazine-l-carboxylate and dihydro-2H-pyran-4(3H)-
one for 4'-
chlorobipheny1-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 105B
(S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-amine
The title compound was prepared by substituting EXAMPLE 105A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 105C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3-
nitro-4- { R3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 105B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz, dimethylsulfoxide-d6)
8
8.68 (br s, 1H), 8.54 (br s, 1H), 8.02 (d, 1H), 7.77 (m, 1H), 7.50 (m, 3H),
7.34 (d, 2H), 7.03
(m, 3H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.19 (d, 1H), 3.98 (m, 2H), 3.90 (m,
2H), 3.52 (m, 2H),
3.09 (s, 2H), 3.05 (m, 4H), 2.77 (m, 2H), 2.60 (m, 2H), 2.16 (m, 6H), 1.95 (m,
2H), 1.65 (m,
5H), 1.50 (m, 3H), 1.38 (m, 2H), 0.94 (s, 6H).
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EXAMPLE 106
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 5-
cyano-6- Rtetrahydro-2H-pyran-4-ylmethyBaminolpyridin-3-y1 } sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 106 A
5-Bromo-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
The title compound was prepared by substituting (tetrahydro-2H-pyran-4-
yl)methanamine for EXAMPLE 3L in EXAMPLE 61A.
EXAMPLE 106B
5-cyano-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 106A for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 106C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 5-
cyano-6- Rtetrahydro-2H-pyran-4-ylmethyBaminolpyridin-3-y1 } sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 106B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.62 (s, 1H),
8.55 (s,
1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.87 (s, 1H), 7.56 (d, 1H), 7.48 (d, 2H),
7.34 (d, 2H), 7.04 (d,
2H), 6.64 (m, 1H), 6.37 (s, 1H), 6.19 (d, 1H), 3.81 (dd, 2H), 3.25 (m, 4H),
3.04 (s, 4H), 2.74
(s, 2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.87 (m, 1H), 1.53 (m, 2H), 1.37 (t, 2H),
1.18 (m, 2H),
0.91 (s, 6H).
EXAMPLE 107
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
({ 4- R1,1-dioxidothiomorpholin-4-yl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 107A
3-nitro-4-(4-aminothiomorpholine-1,1-dioxide)benzenesulfonamide
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The title compound was prepared by substituting 4-aminothiomorpholine-1,1-
dioxide for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 107B
Trans-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
( { 4- [(1,1-dioxidothiomorpholin-4-yl)amino1 -3-nitrophenyl}sulfony1)-2-(1H-
pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 107A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.64 (s, 1H),
9.58 (s,
1H), 8.50 (s, 1H), 8.02 (d, 1H), 7.78 (m, 2H), 7.50 (m, 3H), 7.34 (d, 2H),
7.04 (d, 2H), 6.66
(dd, 1H), 6.38 (s, 1H), 6.19 (d, 1H), 3.48 (m, 4H), 3.23 (m, 4H), 3.05 (s,
4H), 2.73 (d, 2H),
2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 108
N-[(4-{ [(4-aminotetrahydro-2H-pyran-4-yl)methyl[amino}-3-
nitrophenyl)sulfony11-4-(4- { [2-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo[2,3-
b[pyridin-5-yloxy)benzamide
EXAMPLE 108A
4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 4-(aminomethyl)tetrahydro-2H-
pyran-4-amine for (tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
EXAMPLE 108B
N- [(4- { [(4-aminotetrahydro-2H-pyran-4-yl)methyl[amino}-3-
nitrophenyl)sulfonyll-4-(4- { [2-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo[2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 108A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.55 (s,
1H), 8.45 (s, 2H), 7.95 (d, 1H), 7.75-7.77 (m, 1H), 7.57 (d, 2H), 7.44 (s,
1H), 7.34 (d, 2H),
7.09 (d, J = 8.85 Hz, 1H), 7.05 (d, 2H), 6.69 (dd, 1H), 6.33 (d, 1H), 6.22 (d,
1H), 3.59-3.71
(m, 6H), 3.01 (s, 4H), 2.73 (s, 2H), 2.15-2.19 (m, 6H), 1.95 (s, 2H), 1.71-
1.74 (m, 2H), 1.59-
1.61 (m, 1H), 1.38 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 109
Trans-4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-N-
(1 5-cyano-6- R4-morpholin-4-ylcyclohexyl)aminolpyridin-3-yll sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 109A
Trans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 9B for EXAMPLE 3L
in EXAMPLE 61A.
EXAMPLE 109B
Trans-5-cyano-6-(4-morpholinocyclohexylamino)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 109A for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 109C
Trans-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-N-
(1 5-cyano-6- R4-morpholin-4-ylcyclohexyl)aminolpyridin-3-yll sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 109B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.59 (s, 1H),
8.56 (d,
1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H), 7.47 (m, 2H), 7.34 (d, 2H),
7.04 (d, 2H), 6.64
(dd, 1H), 6.36 (d, 1H), 6.19 (d, 1H), 4.00 (m, 1H), 3.65 (m, 4H), 3.28 (m,
4H), 3.03 (m, 4H),
2.73 (m, 4H), 2.16 (m, 6H), 1.90 (m, 6H), 1.40 (m, 6H), 0.93 (s, 6H).
EXAMPLE 110
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(13-
cyano-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl I sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 52B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.71 (s, 1H),
11.23
(s, 1H), 8.08 (d, 1H), 7.91 (d, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.52 (m,
2H), 7.34 (m, 2H),
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7.16 (s, 1H), 7.04 (m, 2H), 6.83 (d, 1H), 6.68 (dd, 1H), 6.43 (dd, 1H), 6.16
(d, 1H), 3.83 (dd,
2H), 3.23 (m, 2H), 3.12 (t, 2H), 3.06 (m, 4H), 2.73 (m, 2H), 2.15 (m, 6H),
1.95 (s, 2H), 1.82
(m, 1H), 1.58 (m, 2H), 1.38 (m, 2H), 1.18 (m, 2H), 0.92 (s, 6H).
EXAMPLE 111
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ R1S,3R)-3-morpholin-4-ylcyclopentyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 111A
benzyl (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentylcarbamate
(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (1.03 g),
diphenylphosphoryl azide (DPPA, 1.00 mL), triethylamine (0.929 mL), and benzyl
alcohol
(0.931 mL) were combined in toluene (10 mL) and stirred at 100 C for 24 hours.
The solution
was cooled and chromatographed on silica gel using 10% ethyl acetate/ hexanes
to give the
pure product.
EXAMPLE 111B
benzyl (1S,3R)-3-aminocyclopentylcarbamate
The title compound was prepared by substituting EXAMPLE 111A for
EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 111C
benzyl (1S,3R)-3-morpholinocyclopentylcarbamate
A solution of EXAMPLE 111B (400 mg), 1-bromo-2-(2-bromoethoxy)ethane
(0.246 mL), and triethylamine (0.595 mL) in N,N-dimethylformamide (6 mL) was
stirred at
70 C for 24 hours. The solution was cooled and poured into ethyl acetate (200
mL). The
solution was extracted with 3x water, washed with brine, concentrated, and
chromatographed
on silica gel using 10% methanol/ethyl acetate to give the pure product.
EXAMPLE 111D
(1S,3R)-3-morpholinocyclopentanamine
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EXAMPLE 111C (300 mg) and ethanol (20 ml) were added to wet 20%
Pd(OH)2-C (60.0 mg) in a 50 mL pressure bottle and stirred for 8 hours at 30
psi. The
mixture was filtered through a nylon membrane and condensed to give the
product.
EXAMPLE 111E
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ R1S,3R)-3-morpholin-4-ylcyclopentyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE
1E and EXAMPLE 111D for EXAMPLE 1F in EXAMPLE 1G. 1H NMR
(dimethylsulfoxide-d6) 8 11.65 (s, 1H), 8.45 (d, 1H), 8.28 (dd, 1H), 7.97 (d,
1H), 7.68 (d,
1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.92 (dd, 1H),
6.85 (dd, 1H), 6.33
(s, 1H), 6.22 (s, 1H), 4.08 (m, 1H), 3.60 (br s, 4H), 3.06 (br s, 4H), 2.73
(br s, 3H), 2.48 (m,
4H), 2.28 (m, 1H), 2.18 (m, 6H), 2.07 (m, 1H), 1.95 (s, 2H), 1.79 (m, 2H),
1.63 (m, 2H), 1.38
(t, 2H), 0.93 (s, 6H).
EXAMPLE 112
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- 11(4-
{ R1R,3S)-3-morpholin-4-ylcyclopentyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 112A
tert-butyl (1R,3S)-3-aminocyclopentylcarbamate
The title compound was prepared by substituting EXAMPLE 111A for
EXAMPLE 111C in EXAMPLE 111D.
EXAMPLE 112B
tert-butyl (1R,3S)-3-morpholinocyclopentylcarbamate
The title compound was prepared by substituting EXAMPLE 112A for
EXAMPLE 111B in EXAMPLE 111C.
EXAMPLE 112C
(1R,3S)-3-morpholinocyclopentanamine
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The title compound was prepared by substituting EXAMPLE 112B for
EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 112D
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(1R,3S)-3-morpholin-4-ylcyclopentyll amino1-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 112C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (dimethylsulfoxide -
d6) 8 11.35 (s, 1H), 8.51 (d, 1H), 8.44 (dd, 1H), 8.00 (d, 1H), 7.77 (d, 1H),
7.50 (d, 1H), 7.48
(s, 2H), 7.34 (d, 2H), 7.04 (d, 2H), 7.02 (dd, 1H), 6.67 (dd, 1H), 6.37 (dd,
1H), 6.21 (d, 1H),
4.11 (m, 1H), 3.61 (br s, 4H), 3.06 (br s, 4H), 2.73 (br s, 3H), 2.50 (m, 4H),
2.28 (m, 1H),
2.18 (m, 6H), 2.06 (m, 1H), 1.95 (s, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.38 (t,
2H), 0.92 (s,
6H).
EXAMPLE 113
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(morpholin-2-ylmethyBaminol-3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 113A
tert-butyl 2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
The title compound was prepared by substituting tert-butyl 2-
(aminomethyl)morpholine-4-carboxylate for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
EXAMPLE 113B
tert-butyl 2-((4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
nitrophenylamino)methyl)morpholine-4-carboxylate
The title compound was prepared by substituting EXAMPLE 113A for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G, with the exception that the
product was purified on a silica gel column eluted with 4% methanol in
dichloromethane.
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EXAMPLE 113C
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
Rmorpholin-2-ylmethyBaminol-3-nitrophenyl I sulfony1)-2-(1H-pyrrolo [2,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 113B for EXAMPLE
66B in EXAMPLE 66C. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.60 (s, 1H),
8.55 (br,
s, 1H), 8.51 (s, 1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 7.49-7.46 (m,
2H), 7.34 (d, 2H),
7.07 (d, 1H), 7.04(d, 2H), 6.66 (dd, 1H), 6.36 (s, 1H), 6.20 (d, 1H), 4.00
(dd, 1H), 3.91 (m,
1H), 3.70 (t, 1H), 3.60 (m, 1H), 3.58 (m, 1H), 3.32 (m, 1H), 3.16 (d, 1H),
3.05 (m, 4H), 2.98
(td, 1H), 2.86 (t, 1H), 2.73 (s, 2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
EXAMPLE 114
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-1-
y1)-N-({3-
nitro-4- Rtetrahydrofuran-3-ylmethyl)aminolphenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 114A
3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting 3-aminomethyl-tetrahydrofuran
for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 114B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(1 3-
nitro-4- Rtetrahydrofuran-3-ylmethyl)aminolphenyl I sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 114A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.68 (s, 1H),
11.42
(bs, 1H), 8.63 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.53-7.48
(m, 3H), 7.34
(d, 2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d,
1H), 3.82-3.79 (m,
1H),3.71 (t, 1H), 3.62 (dd, 1H), 3.50 (dd, 1H), 3.38 (m, 1H), 3.32 (m, 1H),
3.07 (m, 4H), 2.76
(s, 2H), 2.58 (m, 1H), 2.25-2.00 (m, 6H), 1.98 (m, 1H), 1.95 (s, 2H), 1.65 (m,
1H), 1.38 (t,
2H), 0.92 (s, 6H).
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EXAMPLE 115
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-114-
(11-1cis-3-fluorotetrahydro-2H-pyran-4-yllpiperidin-4-yllamino)-3-nitrophenyll
sulfony11-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 115A
Cis-tert-butyl 1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate
The title compound was prepared as a racemate of the cis diastereomer by
substituting
tert-butyl piperidin-4-ylcarbamate for piperidin-4-ol and 3-fluorodihydro-2H-
pyran-4(3H)-
one (prepared by the method described in US2005/0101628A1) for dihydro-2H-
pyran-4(3H)-
one) in EXAMPLE 84A.
EXAMPLE 115B
Cis-1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine
EXAMPLE 115A (0.29 g) was dissolved in CH2C12 (9 mL), then 4N HC1 in dioxane
(4 mL) was added and the reaction stirred at room temperature for 16 hours.
The reaction was
diluted with CH2C12 (30 mL), then 4N aqueous NaOH (5 mL) was added. After
shaking and
separating the layers the aqueous layer was saturated with solid NaC1 and
extracted with
more CH2C12 (10 mL). The combined organic layers were dried over Na2SO4. After
filtration
and concentration the amine was used with no further purification.
EXAMPLE 115C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyllpiperazin-1-
y1)-N-114-
(11-1cis-3-fluorotetrahydro-2H-pyran-4-yllpiperidin-4-yllamino)-3-
nitrophenyllsulfony11-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 115B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
11.64 (s, 1H), 8.54 (d, 1H), 8.43 (br d, 1H), 8.03 (d, 1H), 7.80 (dd, 1H),
7.50 (m, 3H), 7.35
(d, 2H), 7.11 (d, 1H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.38 ( m, 1H), 6.20 (d,
1H), 4.92 (d, 1H),
3.95 (m, 2H), 3.70 (v br m, 1H), 3.50, 3.40, 3.30 (all m, total 5H), 3.05,
3.00 (both v br m,
total 5H), 2.74 (s, 2H), 2.55 (v br m, 1H), 2.18 (br m, 6H), 1.95 (m, 4H),
1.88 (ddd, 1H), 1.63
(v br m, 3H), 1.38 (t, 2H), 0.92 (s, 6H).
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EXAMPLE 116
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 3-
nitro-4- R1-tetrahydro-2H-pyran-4-ylazetidin-3 -yl)aminolphenyl } sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 116A
1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine
Tert-butyl azetidin-3-ylcarbamate (0.46 g), dihydro-2H-pyran-4(3H)-one (0.29
g) and
sodium triacetoxyborohydride (0.85 g) were stirred together in dichloromethane
(5 mL)
overnight. The reaction was poured into dichloromethane (50 mL) and saturated
aqueous
NaHCO3 solution (25 mL). The organic layer was separated, washed with brine
(25 mL),
dried over Na2SO4, filtered, and concentrated. Silica gel chromatography
(GraceResolv 12 g)
eluting with a gradient of 0.75% to 7.5% methanol/dichloromethane over 20
minutes gave the
Boc-protected intermediate. Treatment with HC1 (4.0M in dioxane, 2 mL) and
methanol (1
mL) for 1 hour gave the title compound after concentration as the di-HC1 salt.
EXAMPLE 116B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R1-tetrahydro-2H-pyran-4-ylazetidin-3 -yl)aminolphenyl } sulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
A suspension of 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-N-(4-chloro-3-
nitrophenylsulfony1)-4-(4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazinl-yl)benzamide (0.180 g), 1-(tetrahydro-2H-pyran-4-
yl)azetidin-3-
amine (0.078 g), and triethylamine (0.159 mL) in dioxane (2 mL) was degassed
with nitrogen
for 30 seconds then sealed. The reaction was heated to 110 C. After stirring
for 16 hours,
more triethylamine (10 equivalents total) and dimethylsulfoxide (1 mL) were
added and the
reaction stirred for an additional 18 hours at 110 C. The reaction was cooled,
diluted with
water (50 mL) and extracted with dichloromethane (2 x 150 mL). The organic
layer was
dried over magnesium sulfate, filtered and concentrated. Silica gel
chromatography
(GraceResolv 12 g) eluting with a gradient of 0.75% to 7.5%
methanol/dichloromethane
(Flow = 36 mL/minutes) gave the title compound. 1H NMR (300 MHz,
dimethylsulfoxide-d6)
6 11.59 (s, 1H), 8.49 (d, 1H), 8.40 (s, 1H), 7.97 (d, 1H), 7.77 (s, 1H), 7.47
(dd, 3H), 7.34 (d,
2H), 7.04 (d, 2H), 6.90 ¨ 6.78 (m, 1H), 6.65 (d, 1H), 6.35 (s, 1H), 6.21 (s,
1H), 4.47 ¨ 4.23
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(m, 1H), 3.83 (s, 3H), 3.05 (s, 6H), 2.73 (s, 2H), 2.18 (s, 8H), 1.95 (s, 2H),
1.68 (s, 2H), 1.38
(s, 2H), 1.24 (s, 4H), 0.92 (s, 6H).
EXAMPLE 117
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 3-
nitro-4- R1-tetrahydrofuran-3-ylazetidin-3-yl)aminolphenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 117A
1-(tetrahydrofuran-3-yl)azetidin-3-amine
Tert-butyl azetidin-3-ylcarbamate (0.550 g), dihydrofuran-3(2H)-one (0.412 g)
and
sodium triacetoxyborohydride (1.015 g) were stirred together in
dichloromethane (5 mL).
After stirring overnight, the reaction was poured into saturated aqueous
NaHCO3 solution (25
mL) and extracted with dichloromethane (50 mL). The organic layer was washed
with brine
(25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (GraceResolv 12 g) eluting with a gradient of 0.5% to 7.5%
methanol/dichloromethane over 30 minutes gave tert-butyl 1-(tetrahydrofuran-3-
yl)azetidin-
3-ylcarbamate. The resulting material was treated with HC1/dioxane for 1 hour,
and then
concentrated to give the title compound.
EXAMPLE 117B
3-nitro-4-(1-(tetrahydrofuran-3-yl)azetidin-3-ylamino)benzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (0.084 g), 1-(tetrahydrofuran-3-yl)azetidin-
3-
amine
(0.090 g) and triethylamine (0.266 ml) in tetrahydrofuran (3 mL) was heated to
60 C. After
stirring for 4 hours, the reaction was cooled, the tetrahydrofuran was removed
and the residue
was partitioned between dichloromethane (200 mL) and water (20 mL). The
organic layer
was separated, washed with brine (25 mL), dried over magnesium sulfate,
filtered, and
concentrated to give the title compound.
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EXAMPLE 117C
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R1-tetrahydrofuran-3-ylazetidin-3-yl)aminolphenyl } sulfonyl)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 117B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz, CDC13) 6
10.39 - 9.79 (m, 1H), 9.17 (s, 1H), 8.87 (d, 1H), 8.51 (d, 1H), 8.15 (dd, 2H),
7.94 (d, 1H),
7.68 (d, 1H), 7.48 - 7.42 (m, 1H), 7.23 (d, 2H), 6.91 (d, 2H), 6.69 (d, 1H),
6.54 (dd, 2H), 5.99
(d, 1H), 4.29 (d, 1H), 4.01 - 3.73 (m, 4H), 3.66 (d, 2H), 3.08 (s, 6H), 2.76
(s, 2H), 2.21 (s,
6H), 2.03 - 1.83 (m, 3H), 1.64 (s, 2H), 1.42 (d, 2H), 0.93 (s, 6H).
EXAMPLE 118
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { l3 -
nitro-44 { R3R)-1-tetrahydro-2H-pyran-4-ylp yrrolidin-3-yll methyl }
amino)phenyll sulfonyl I -
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 118A
(R)-tert-butyl (1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate
The title compound was prepared by substituting (S)-tert-butyl pyrrolidin-3-
ylmethylcarbamate for tert-butyl piperazine-l-carboxylate and dihydro-2H-pyran-
4(3H)-one
for 4'-chlorobipheny1-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 118B
(R)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine
The title compound was prepared by substituting EXAMPLE 118A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 118C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { l3 -
nitro-4-( { R3R)-1-tetrahydro-2H-pyran-4-ylp yrrolidin-3-yll methyl }
amino)phenyll sulfonyl I -
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 118B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
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11.57 (s, 1H), 8.59 (br s, 1H), 8.45 (br s, 1H), 8.02 (d, 1H), 7.95 (m, 1H),
7.71 (m, 1H), 7.56
(d, 1H), 7.45 (m, 1H), 7.35 (m, 3H), 7.05 (m, 2H), 6.90 (br s, 1H), 6.64 (d,
1H), 6.33 (m, 1H),
6.22 (m, 1H), 3.90 (m, 2H), 3.44 (m, 2H), 3.27 (m, 4H), 3.02 (m, 5H), 2.73 (m,
3H), 2.59 (m,
2H), 2.19 (m, 6H), 1.95 (m, 2H), 1.85 (m, 2H), 1.64 (m, 1H), 1.50 (m, 2H),
1.39 (m, 2H),
1.23 (m, 1H), 0.94 (s, 6H).
EXAMPLE 119
4-(4-{ [2-(4-chloropheny1)-5,5-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R4-fluorotetrahydro-2H-pyran-4-y1)methoxyl -3 -nitrophenyl I sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
75F and EXAMPLE 37D in place of EXAMPLE 3J and EXAMPLE 11B, respectively. 1H
NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 8.39 (s, 1H), 8.08 (d,
1H), 8.04 (d,
1H), 7.41 - 7.59 (m, 4H), 7.35 (d, 2H), 7.08 (d, 2H), 6.68 (dd, 1H), 6.37 -
6.43 (m, 1H), 6.20
(s, 1H), 4.38 (d, 2H), 3.73 - 3.82 (m, 2H), 3.54 - 3.63 (m, 2H), 3.09 (s, 4H),
2.81 (s, 2H), 2.16
- 2.39 (m, 5H), 1.94 (s, 2H), 1.79 - 1.93 (m, 4H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 120
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide
EXAMPLE 120A
Trans-4-(aminomethyl)cyclohexanol
Tert-butyl ((lr,4r)-4-hydroxycyclohexyl)methylcarbamate (1 g) in
dichloromethane
(10 mL) was treated with trifluoroacetic acid (5 mL) at 0 C for 10 minutes and
at room
temperature for 30 minutes. The reaction mixture was concentrated and dried in
vacuo to
provide the title compound as a trifluoroacetic acid salt.
EXAMPLE 120B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide
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A mixture of EXAMPLE 53A (211 mg), EXAMPLE 120A (104 mg) and N-ethyl-N-
isopropylpropan-2-amine (0.3 mL) in dimethylsulfoxide (2 mL) was heated at 150
C in a
Biotage Initiator microwave synthesizer for 1.5 hours and concentrated. The
residue was
purified by reverse phase HPLC on a C18 column using a gradient of 40-60%
acetonitrile in
0.1% trifluoroacetic acid water to give the title compound as a
trifluoroacetate salt. The
trifluoroacetic acid salt was dissolved in dichloromethane (30 mL) and washed
with 50%
aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered,
and
concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-
d6) 8 11.69
(s, 1H), 11.41 (s, 1H), 8.61 (t, 1H), 8.53 - 8.58 (m, 1H), 8.04 (d, 1H), 7.76 -
7.83 (m, 1H),
7.47 - 7.56 (m, 3H), 7.34 (d, 2H), 7.07 - 7.11 (m, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (dd,
1H), 6.19 (d, 1H), 4.82 - 4.99 (m, 1H), 4.50 (d, 1H), 3.26 - 3.31 (m, 2H),
3.23 (t, 1H), 3.07 (s,
4H), 2.76 (s, 2H), 2.10 - 2.28 (m, 6H), 2.05 (dd, 1H), 1.95 (s, 2H), 1.84 (t,
2H), 1.52 - 1.76
(m, 2H), 1.41 - 1.51 (m, 1H), 1.38 (t, 2H), 0.95 - 1.25 (m, 4H), 0.92 (s, 6H)
EXAMPLE 121
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide
EXAMPLE 121A
(4-methoxycyclohexyl)methanol
4-Methoxycyclohexanecarboxylic acid (7 g) in tetrahydrofuran (20 mL) was
treated
with 1 M (in tetrahydrofuran) borane-tetrahydrofuran complex (100 mL)
overnight. The
mixture was concentrated and the residue was dissolved in methanol (100 mL)
and
concentrated HC1 (10 mL). The resulting mixture was stirred for 1 hour and
concentrated.
The residue was dissolved in dichloromethane and washed with water. The
organic layer was
dried over Na2SO4, filtered, and concentrated to give the title compound.
EXAMPLE 121B
4-((4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with EXAMPLE 121A.
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EXAMPLE 121C
4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide
Separation of the cis and trans mixture of EXAMAPLE 121B on a reverse phase
HPLC (gradient: 40-55% acetonitrile in 0.1% TFA in water over 25 minutes)
provided the
title compound.
EXAMPLE 121D
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-
nitrophenylsulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
121C in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69
(s,
1H), 11.39 (s, 1H), 8.34 (s, 1H), 7.96 - 8.07 (m, 2H), 7.48 - 7.56 (m, 3H),
7.31 - 7.42 (m, 3H),
7.04 (d, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.39
(s, 1H), 3.20 (s,
3H), 3.09 (s, 4H), 2.82 (s, 2H), 2.09 - 2.34 (m, 6H), 1.96 (s, 2H), 1.78 -
1.86 (m, 3H), 1.54
(dd, 2H), 1.28 - 1.46 (m, 6H), 0.92 (s, 6H)
EXAMPLE 122
Cis-4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-
1-y1)-N-
11(4-114-(cyclopropylamino)cyclohexyll amino1-3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 122A
Cis-tert-butyl-4-(cyclopropylamino)cyclohexylcarbamate
The title compound was prepared by substituting tert-butyl 4-
oxocyclohexylcarbamate
for 4'-chlorobipheny1-2-carboxaldehyde and cyclopropylamine for tert-butyl
piperazine-l-
carboxylate in EXAMPLE 1A.
EXAMPLE 122B
cis-N1-cyclopropylcyclohexane-1,4-diamine bis(2,2,2-trifluoroacetate)
The title compound was prepared by substituting EXAMPLE 122A for EXAMPLE
39A in EXAMPLE 39B.
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EXAMPLE 122C
Cis-4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
R4- { 1L4-(cyclopropylamino)cyclohexyll amino } -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 122B for EXAMPLE
100B in EXAMPLE 100C. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.28 (d,
1H),
8.59 (d, 1H), 8.44 (d, 1H), 8.37 (dd, 1H), 8.12 (d, 1H), 7.67 (t, 2H), 7.43
(t, 2H), 7.07 (d, 2H),
6.90 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.50 (dd, 1H), 3.56 - 3.63 (m, 1H),
3.02 - 3.08 (m,
4H), 2.77 (s, 3H), 2.26 (t, 2H), 2.10 - 2.16 (m, 4H), 2.06 (ddd, 1H), 1.97 (s,
2H), 1.74 - 1.82
(m, 2H), 1.61 - 1.71 (m, 5H), 1.39 (t, 2H), 0.93 (s, 6H), 0.39 - 0.44 (m, 4H).
EXAMPLE 123
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
R3 -nitro-4- { [4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 123A
Trans-tert-buty1-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexylcarbamate
The title compound was prepared by substituting trans-tert-buty1-4-
aminocyclohexylcarbamate for tert-butyl piperazine-l-carboxylate and dihydro-
2H-pyran-
4(3H)-one for 4'-chlorobipheny1-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 123B
trans-N1-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine bis(2,2,2-
trifluoroacetate)
The title compound was prepared by substituting EXAMPLE 123A for EXAMPLE
39A in EXAMPLE 39B.
EXAMPLE 123C
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
R3-nitro-4- { [4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 123B for EXAMPLE
100B in EXAMPLE 100C. 1H NMR (500 MHz, pyridine-d5) 8 13.01 (s, 1H), 9.28 (d,
1H),
8.48 (d, 1H), 8.38 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H), 7.67 - 7.69 (m, 2H),
7.44 (d, 2H), 7.08
(d, 2H), 6.91 (d, 1H), 6.78 (dd, 1H), 6.59 (d, 1H), 6.48 (dd, 1H), 4.01 (d,
2H), 3.44 - 3.49 (m,
1H), 3.37 - 3.43 (m, 2H), 3.01 - 3.09 (m, 5H), 2.85 (t, 1H), 2.78 (s, 2H),
2.27 (t, 2H), 2.13 -
2.18 (m, 4H), 2.05 (t, 4H), 1.97 (s, 2H), 1.93 (d, 2H), 1.52 - 1.60 (m, 2H),
1.44 - 1.50 (m,
2H), 1.39 (t, 2H), 1.25 - 1.34 (m, 2H), 0.94 (s, 6H).
EXAMPLE 124
Trans-N-( 15-bromo-6-R4-morpholin-4-ylcyclohexyBoxylpyridin-3-yll sulfony1)-4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 124A
Trans-4-morpholinocyclohexanol
Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07 g)
and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile (20 mL).
The reaction
mixture was heated at 60 C overnight. The organic solvent was removed under
vacuum. The
residue was purified with flash column chromatography on silica gel eluting
with 7%-10%
methanol in dichloromethane to give the title compound.
EXAMPLE 124B
Trans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 124A for (tetrahydro-
2H-pyran-4-yl)methanol and EXAMPLE 36A for 4-fluoro-3-nitrobenzenesulfonamide
in
EXAMPLE 24A.
EXAMPLE 124C
Trans-N-( 15-bromo-6-R4-morpholin-4-ylcyclohexyBoxylpyridin-3-yll sulfony1)-4-
(4- { 1L244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 124B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.56 (m,
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2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.12 (m, 1H),
7.04 (d, 2H), 6.67
(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37 (m,
2H), 3.24 (m, 2H),
3.07 (m, 4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s, 3H), 1.80 (m,
4H), 1.38 (t,
2H), 1.27 (m, 2H), 0.92 (s, 6H).
EXAMPLE 125
Trans-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-N-
({ 4- [(4-methoxycyclohexyl)methoxy1-3-nitrophenyl}sulfony1)-2-(1H-pyrrolo[2,3-
b[pyridin-
5-yloxy)benzamide
EXAMPLE 125A
4-(((trans)-4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide
Separation of the cis and trans mixture of EXAMAPLE 121B on a reverse phase
HPLC provided the title compound.
EXAMPLE 125B
Trans-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-N-
({ 4- [(4-methoxycyclohexyl)methoxy1-3-nitrophenyl}sulfony1)-2-(1H-pyrrolo[2,3-
b[pyridin-
5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
125A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.68
(s,
1H), 8.34 (s, 1H), 7.96 - 8.09 (m, 2H), 7.51 (dd, 3H), 7.32 - 7.39 (m, 3H),
7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.24 (s, 3H), 3.00 - 3.15
(m, 5H), 2.83 (s,
2H), 2.09 - 2.36 (m, 6H), 2.03 (d, 2H), 1.96 (s, 2H), 1.77 - 1.86 (m, 2H),
1.73 (s, 1H), 1.39 (t,
2H), 1.02 - 1.17 (m, 4H), 0.92 (s, 6H)
EXAMPLE 126
tert-butyl 4-{ [4-({ [4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-2-(1H-pyrrolo[2,3-blpyridin-5-yloxy)benzoyll
aminolsulfony1)-2-
nitrophenoxylmethyll-4-fluoropiperidine-l-carboxylate
EXAMPLE 126A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
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1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) in
tetrahydrofuran (5
mL) was treated with 1.0 N LiA1H4 in THF (2.54 mL) at 0 C. The reaction
mixture was
stirred at room temperature for 2 hours. Water (0.6 mL) was added to the
reaction mixture
drop-wise, followed by 2 N aqueous NaOH (0.2 mL). The reaction was stirred for
another 1
hour. The solid was removed by filtration via a pack of Celite and washed with
ethyl acetate.
The filtrate was washed with brine, dried over MgSO4, filtered, and
concentrated to give the
product.
EXAMPLE 126B
tert-butyl 4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 126A for (tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 126C
tert-butyl 4-{ [4-(1 [4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yll methyl } piperazin-l-y1)-2-(1H-pyrrolo [2,3-blpyridin-5-yloxy)benzoyll
amino I sulfony1)-2-
nitrophenoxyl methyl I -4-fluoropiperidine-1-carboxylateyl)oxylbenzamide
The title compound was prepared by substituting EXAMPLE 126B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s,
1H), 8.36 (s, 2H), 8.02-8.06 (m, 2H), 7.49-7.53 (m, 3H), 7.40 (d, 1H), 7.35
(d, 2H), 7.04 (d,
1H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.36 (d, 2H), 3.83-3.85 (m,
2H), 3.09 (s, 4H),
2.33 (s, 2H), 2.27-2.32 (m, 4H), 2.13-2.16 (m, 2H), 1.96 (s, 2H), 1.83-1.92
(m, 2H), 1.67-
1.75 (m, 2H), 1.38-1.41 (m, 11H), 0.92 (s, 6H).
EXAMPLE 127
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R4-fluoropiperidin-4-y1)methoxyl -3 -nitrophenyl I sulfony1)-2-(1H-pyrrolo
[2,3 -blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 126C for
EXAMPLE 1A in EXAMPLE 1B. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.50 (s,
1H), 8.14 (d, 1H), 7.90 (d, 2H), 7.80 (dd, 1H), 7.60 (d, 1H), 7.40 (t, 1H),
7.35 (d, 2H), 7.25 (t,
1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.30 (dd, 1H), 6.26 (d, 1H),
4.28 (d, 2H), 3.10-
3.13 (m, 2H), 2.91-3.00 (m, 6H), 2.73 (s, 2H), 1.96-2.02 (m, 4H), 1.77-1.89
(m, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
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EXAMPLE 128
Trans-4- (4-112- (4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll
methyllpiperazin-1-y1)-N-
R3-nitro-4-114-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-
yl)cyclohexyll aminolphenyl)sulfonyll -2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 128A
tert-butyl 4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate
The title compound was prepared by substituting tert-butyl piperazine-l-
carboxylate
for morpholine and dihydro-2H-pyran-4(3H)-one for tert-butyl 4-
oxocyclohexylcarbamate in
EXAMPLE 39A.
EXAMPLE 128B
1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride
To a solution of EXAMPLE 128A (3.92 g) in ether was added HC1 (25 ml, 2M in
ether) and the reaction mixture was stirred for 16 hours at room temperature.
The solid
product was filtered off, dried and used in next step without further
purification.
EXAMPLE 128C
Trans-tert-buty1-4-(4-fletrahydro-2H-pyran-4-y0piperazin-1-
yl)cyclohexylcarbamate
The title compound was prepared by substituting EXAMPLE 128B for morpholine in
EXAMPLE 39A.
EXAMPLE 128D
trans-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexanamine tris(2,2,2-

trifluoroacetate)
The title compound was prepared by substituting EXAMPLE 128C for EXAMPLE
39A in EXAMPLE 39B.
EXAMPLE 128E
Trans-4- (4-112- (4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll
methyllpiperazin-1-y1)-N-
1(3-nitro-4-114-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-
yl)cyclohexyllaminolphenyl)sulfonyll-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 128D for EXAMPLE
100B in EXAMPLE 100C. 1H NMR (500 MHz, pyridine-d5) 8 13.07 (s, 1H), 9.28 -
9.32 (m,
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1H), 8.44 (t, 1H), 8.34 - 8.39 (m, 2H), 8.10 - 8.14 (m, 1H), 7.66 - 7.69 (m,
2H), 7.44 (d, 2H),
7.07 (d, 2H), 6.92 (t, 1H), 6.73 - 6.77 (m, 1H), 6.52 - 6.55 (m, 1H), 6.49 -
6.52 (m, 1H), 3.99
- 4.06 (m, 2H), 3.29 - 3.36 (m, 2H), 3.03 - 3.09 (m, 4H), 2.77 (s, 2H), 2.62
(s, 8H), 2.24 -
2.29 (m, 3H), 2.10 - 2.16 (m, 5H), 2.05 (s, 2H), 1.97 (s, 2H), 1.92 (s, 2H),
1.70 (d, 2H), 1.57
(td, 2H), 1.34 - 1.43 (m, 4H), 1.20 - 1.30 (m, 2H), 0.93 (s, 6H).
EXAMPLE 129
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 1- [2-fluoro-1-(fluoromethyBethyl[piperidin-4-yl}methoxy)-3-
nitrophenyl[sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 129A
(1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol
A suspension of piperidin-4-ylmethanol (0.250 g), sodium triacetoxyborohydride
(0.690 g) and 1,3-difluoropropan-2-one (0.245 g) were stirred together in
dichloromethane.
After stirring overnight the reaction was poured into saturated aqueous NaHCO3
solution (10
mL) and stirred for 15 minutes. The reaction was extracted with
dichloromethane (3 x 25
mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography
(GraceResolv 12 g) eluting with a gradient of 0.75% to 3%
methanol/dichloromethane gave
the title compound.
EXAMPLE 129B
4-((1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methoxy)-3-
nitrobenzenesulfonamide
To a solution of (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol (0.068 g)
in
tetrahydrofuran (1 mL) was added sodium hydride (0.056 g) and the reaction
stirred for 30
minutes at room temperature. 4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was
added in
one portion and stirring was continued for 1 hour. The reaction was poured
into water (20
mL) and extracted with dichloromethane. The pH of the aqueous layer was
adjusted to pH-8
and it was extracted with dichloromethane (50 mL). The organic layer was dried
over
magnesium sulfate, filtered, and concentrated to give the title compound.
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EXAMPLE 129C
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yl[methyl}piperazin-
1-y1)-N- { [4-
( { 1- 1L2-fluoro-1-(fluoromethyBethyl[piperidin-4-yl}methoxy)-3-
nitrophenyl[sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 129B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.67 (s, 1H), 11.47 - 10.98 (m, 1H), 8.33 (d, 1H),
8.03 (d, 2H), 7.50
(dd, 3H), 7.36 (t, 3H), 7.04 (d, 2H), 6.67 (d, 1H), 6.39 (dd, 1H), 6.20 (s,
1H), 4.62 (dd, 4H),
4.06 (d, 2H), 3.18 - 2.71 (m, 11H), 2.20 (d, 6H), 1.96 (s, 2H), 1.73 (d, 3H),
1.35 (d, 4H), 0.92
(s, 6H).
EXAMPLE 130
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(3 -
nitro-4- { [(3R)-1 -tetrahydro-2H-pyran-4-ylpyrrolidin-3-
yflamino}phenyl)sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 130A
(R)-tert-butyl 1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for
4'-
chlorobipheny1-2-carboxaldehyde and (R)-tert-butyl pyrrolidin-3-ylcarbamate
for tert-butyl
piperazine-l-carboxylate in EXAMPLE 1A.
EXAMPLE 130B
(R)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
A solution of EXAMPLE 130A (550 mg) in dichloromethane (25 ml) was cooled in
an ice bath under nitrogen. 2,2,2-Trifluoroacetic acid (8.333 ml) was added
and the reaction
was stirred for 2 hours. The product was obtained by concentration and high
vacuum drying.
EXAMPLE 130C
(R)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-
ylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 130B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
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EXAMPLE 130D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(3 -
nitro-4- { R3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-y11amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
To a solution of EXAMPLE 3J (90 mg), EXAMPLE 130C (64.2 mg), triethylamine
(0.077 ml), N,N-dimethylpyridin-4-amine (38.5 mg) in a mixture of
dichloromethane (5 ml)
and N,N-dimethylformamide (0.5 ml) was added N1-((ethylimino)methylene)-N3,N3-
dimethylpropane-1,3-diamine, hydrochloric acid (60.4 mg) and the mixture was
stirred 18
hours. This was concentrated on high vacuum and the crude was purified by
reverse phase
chromatography with ammonium acetate buffer / acetonitrile. 1H NMR (500 MHz,
pyridine-
d5) 8 13.03 (s, 1H), 9.27 (d, 1H), 8.59 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H),
8.11 (d, 1H), 7.65
- 7.67 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.54
(d, 1H), 6.48 (m,
1H), 4.06 (m, 1H), 3.98 (d, 2H), 3.35 (t, 2H), 3.07 (m, 4H), 2.73 - 2.80 (m,
4H), 2.68 - 2.72
(m, 1H), 2.36 (q, 1H), 2.11 - 2.30 (m, 9H), 1.97 (m, 2H), 1.62 - 1.71 (m, 3H),
1.48 - 1.58 (m,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 131
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f R3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yll amino I -3-
nitrophenyl)sulfony11-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 131A
tert-butyl (3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-
ylcarbamate
The title compound was prepared by substituting 2,2-dimethyldihydro-2H-pyran-
4(3H)-one for 4'-chlorobipheny1-2-carboxaldehyde and (R)-tert-butyl pyrrolidin-
3-
ylcarbamate for tert-butyl piperazine-l-carboxylate in EXAMPLE 1A.
EXAMPLE 131B
(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 131A for EXAMPLE
130A in EXAMPLE 130B.
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EXAMPLE 131C
4-((3R)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 131B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 131D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yll amino I -3-
nitrophenyl)sulfony11-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 131C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d5) 8 13.03 (d, 1H), 9.28 (m,
1H),
8.61 (m, 1H), 8.44 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.64 - 7.68 (m, 2H),
7.44 (d, 2H),
7.07 (d, 2H), 6.89 (m, 1H), 6.76 (dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08
(m, 1H), 3.78 (m,
1H), 3.61 (m, 1H), 3.07 (m, 4H), 2.71 - 2.82 (m, 5H), 2.37 - 2.44 (m, 2H),
2.19 - 2.29 (m,
3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66 (m, 2H), 1.32 - 1.49 (m,
4H), 1.28 (d,
3H), 1.20 (s, 3H), 0.94 (s, 6H).
EXAMPLE 132
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { R3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-y11amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 132A
(S)-tert-butyl 1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for
4'-
chlorobipheny1-2-carboxaldehyde and (S)-tert-butyl pyrrolidin-3-ylcarbamate
for tert-butyl
piperazine-l-carboxylate in EXAMPLE 1A.
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EXAMPLE 132B
(S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 132A for EXAMPLE
130A in EXAMPLE 130B.
EXAMPLE 132C
(S)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-
ylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 132B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMMPLE 132D
4-(4-11L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N- 11(3 -
nitro-4-1 R3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yll
aminolphenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 132C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.04 (m, 1H), 9.27 (d,
1H),
8.58 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H), 7.64 - 7.68 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.88 (d, 1H), 6.75 (dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.06 (m,
1H), 3.98 (d, 2H),
3.36 (t, 2H), 3.07 (m, 4H), 2.68 - 2.80 (m, 5H), 2.36 (m, 1H), 2.09 - 2.29 (m,
9H), 1.97 (s,
2H), 1.62 - 1.72 (m, 3H), 1.48 - 1.60 (m, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 133
4-(4-1112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N- 11(4-
1 R3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yll amino1-3-
nitrophenyl)sulfonyll-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 133A
tert-butyl (3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-
ylcarbamate
The title compound was prepared by substituting 2,2-dimethyldihydro-2H-pyran-
4(3H)-one for 4'-chlorobipheny1-2-carboxaldehyde and (S)-tert-butyl pyrrolidin-
3-
ylcarbamate for tert-butyl piperazine-l-carboxylate in EXAMPLE 1A.
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EXAMPLE 133B
(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 133A for EXAMPLE
130A in EXAMPLE 130B.
EXAMPLE 133C
4-(3S)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-nitro
benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 133B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 133D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f 11(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yll amino I -3 -
nitrophenyl)sulfonyll-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 133C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.03 (d, 1H), 9.28 (m,
1H),
8.61 (m, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.64 - 7.68 (m, 2H),
7.44 (d, 2H),
7.07 (d, 2H), 6.89 (m, 1H), 6.76 (dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08
(m, 1H), 3.78 (m,
1H), 3.61 (m, 1H), 3.07 (m, 4H), 2.71 - 2.82 (m, 5H), 2.37 - 2.44 (m, 2H),
2.19 - 2.29 (m,
3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66 (m, 2H), 1.33 - 1.48 (m,
4H), 1.28 (d,
3H), 1.20 (s, 3H), 0.94 (s, 6H).
EXAMPLE 134
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R4-methylmorpholin-2-yl)methyll amino I -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 134A
4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
A solution of EXAMPLE 113A (0.8 g) in dichloromethane (10 mL) and
trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The
solvents were
evaporated and the residue triturated with diethyl ether. The resulting solid
was dissolved in
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5% aqueous sodium carbonate solution (20 mL). The solution was concentrated to
dryness
and the resulting solid was triturated with a solution of 10% methanol in
dichloromethane
several times. Evaporation of the organic solvents gave the title compound.
EXAMPLE 134B
4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
To a solution of EXAMPLE 134A (158 mg) in anhydrous N,N-dimethylformamide (4
mL) was added sodium carbonate (64 mg) and methyl iodide (78 mg). After
stilling
overnight at room temperature, the mixture was evaporated to dryness. The
crude product
was then absorbed on silica gel (6 g) and purified on a silica gel column
eluting with 10%
methanol in dichloromethane to give the title compound.
EXAMPLE 134C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(4-methylmorpholin-2-y1)methyllaminol-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 134B for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.27 (d,
1H),
8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.65 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.91 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.92 (m,
1H),3.86 (d, 1H), 3.67
(dt, 1H), 3.49-3.39 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 3.71 (m, 1H), 2.49
(d, 1H), 2.26 (m,
2H), 2.16 (s, 3H), 2.14 (m, 4H), 2.03 (dt, 1H), 1.97 (s, 2H), 1.90 (t, 1H),
1.39 (t, 2H), 0.94 (s,
6H).
EXAMPLE 135
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-114-
(114-(2-methoxyethyl)morpholin-2-yllmethyllamino)-3-nitrophenyll sulfony11-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 135A
4-((4-(2-methoxyethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
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The title compound was prepared by substituting 2-methoxyethyl bromide for
methyl
iodide in EXAMPLE 134B.
EXAMPLE 135B
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ [4-(2-methoxyethyl)morpholin-2-yll methyl } amino)-3-nitrophenyllsulfonyl I
-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 135A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 12.98 (s, 1H), 9.26 (d,
1H),
8.88 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.91 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m,
1H),3.87 (d, 1H), 3.70
(dt, 1H), 3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.27 (s, 3H), 3.07 (m, 4H), 2.95
(d, 1H), 2.77 (s,
2H), 2.70 (m, 1H), 2.57 (t, 2H), 2.27-2.07 (m, 8H), 1.97 (s, 2H), 1.39 (t,
2H), 0.94 (s, 6H).
EXAMPLE 136
N- l(4- { R4-acetylmorpholin-2-yl)methyll amino } -3 -nitrophenyl)sulfonyll -4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 136A
4-((4-acetylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting acetic anhydride for methyl
iodide in
EXAMPLE 134B.
EXAMPLE 136B
N- R4- { R4-acetylmorpholin-2-yl)methyll amino } -3 -nitrophenyl)sulfonyll -4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.26 (s,
1H),
8.85 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H), 7.65 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.91 (dd, 1H), 6.75 (dd, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.73 (dd, 1H),
3.93-3.65 (m,
2H), 3.60-3.40 (m, 4H), 3.12 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.70 (m,
1H), 2.57 (t, 2H),
2.14 (s, 3H), 2.27-2.07 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 137
4-(4-11L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N- 11(4-
1 ltrans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yllmethoxy1-3-
nitropheny0sulfonyll -2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 137A
ethyl 4-fluorobut-2-enoate
Ethyl 2-fluoroacetate (21.0 g) in CH2C12 (200 mL) at -78 C was treated
dropwise
over 45 min with a 1.0 M solution of diisobutylaluminum hydride in CH2C12 (200
mL)
maintaining the internal temperature below -70 C. Stirring was continued at -
78 C for 30
minutes and then (carbethoxymethylene)triphenylphosphorane (70.0 g) was added
in one
portion. The reaction mixture was allowed to slowly reach room temperature
while stirring
overnight. It was then quenched with methanol, filtered and concentrated to
give the product
as a mixture of isomers (E/Z = 3:1).
EXAMPLE 137B
Trans-ethyl 1-benzy1-4-(fluoromethyl)pyrrolidine-3-carboxylate
A mixture of N-benzy1-1-methoxy-N-((trimethylsily0methyl)methanamine (4.5 g)
and EXAMPLE 137A (2.5 g) in dichloromethane (50 mL) was cooled to 0 C,
treated
dropwise with trifluoroacetic acid (0.15 mL), stirred for 4 hours at 0 C and
neutralized with
saturated aqueous Na2CO3 solution. The mixture was poured into a separatory
funnel and the
layers separated. The organic layer was washed with water and brine, dried
(MgSO4),
filtered, concentrated and chromatographed on silica gel with 0-20% ethyl
acetate in hexanes
as eluent to give both the cis and trans isomers of the product. Only the
trans diastereomers
were carried on in the following steps.
EXAMPLE 137C
Trans-ethyl 4-(fluoromethyl)pyrrolidine-3-carboxylate
EXAMPLE 137B (0.83 g) in ethanol (9 mL) was treated with 10% Pd/C (0.208 g)
and
ammonium formate (1.97 g), refluxed for 1.5 hours, concentrated, dissolved in
dichloromethane, filtered though a pad of celite rinsing with dichloromethane,
and
concentrated to give the product.
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EXAMPLE 137D
Trans-l-benzyl 3-ethyl 4-(fluoromethyl)pyrrolidine-1,3-dicarboxylate
EXAMPLE 137C (0.44 g) in dioxane (4 mL) and water (4 mL) at 0 C was treated
sequentially with Na2CO3 (0.89 g) and benzyl chloroformate (0.48 mL). The
reaction
mixture was stirred at 0 C for 3 hours and was then allowed to slowly warm to
room
temperature over 1.5 hours. The reaction mixture was diluted with ethyl
acetate, washed with
water and brine, dried (MgSO4), filtered, concentrated and chromatographed on
silica gel
with 10-25% ethyl acetate in hexanes as eluent to give the product.
EXAMPLE 137E
Trans-1-(benzyloxycarbony1)-4-(fluoromethyl)pyrrolidine-3-carboxylic acid
The title compound was prepared by substituting EXAMPLE 137D for EXAMPLE
15G in EXAMPLE 15H.
EXAMPLE 137F
Trans-benzyl 3-(fluoromethyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate
EXAMPLE 137E (0.563 g) in tetrahydrofuran (10 mL) at 0 C was treated dropwise

with a 1 M solution of borane in tetrahydrofuran (4 mL), stirred for 3 hours
and then slowly
quenched with saturated aqueous NH4C1 solution. The reaction mixture was
diluted with
ethyl acetate, washed with water and brine, dried (MgSO4), filtered and
concentrated to give
the product.
EXAMPLE 137G
Trans-benzyl 3-(fluoromethyl)-4-((2-nitro-4-
sulfamoylphenoxy)methyl)pyrrolidine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 137F for (tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 137H
Trans-4-((4-(fluoromethyl)pyrrolidin-3-yl)methoxy)-3-nitrobenzenesulfonamide
EXAMPLE 137G (0.232g) in acetic acid (2.5 ml) was treated with hydrobromic
acid
(33 wt % in acetic acid) (0.875 mL) at ambient temperature, stirred for 1 hour
and
concentrated. The product was free-based using a MEGA BE-SCX column with 1:1
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CH2C12/methanol as eluent for the hydrobromic acid and acetic acid. The
product was
released from the column with 10% (7 M ammonia in methanol) in CH2C12 as
eluent.
EXAMPLE 1371
Trans-4-((4-(fluoromethyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 137H for tert-butyl
piperazine-l-carboxylate and 3-oxetanone for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A.
EXAMPLE 137J
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-
y1)-N-1(4-
Iltrans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yllmethoxyl-3-
nitrophenyl)sulfonyll -2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 1371 for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.35 (d,
1H), 8.03 (m, 2H), 7.51 (m, 3H), 7.37 (m, 3H), 7.04 (m, 2H), 6.67 (dd, 1H),
6.39 (dd, 1H),
6.21 (d, 1H), 4.45 (m, 6H), 4.21 (d, 2H), 3.62 (m, 1H), 3.08 (m, 4H), 2.72 (m,
5H), 2.31 (m,
9H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 138
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(4-fluorotetrahydro-2H-pyran-4-y1)methyll amino1-3-nitrophenyl)sulfonyll -2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 138A
(4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate
A mixture of EXAMPLE 37C (1.4 g), methanesulfonyl chloride (1.054 mL),
triethylamine (2.99 mL), and 4-dimethylaminopyridine (0.051 g) in CH2C12 (20
mL) was
stirred at 0 C for 2 hours, concentrated and chromatographed on silica gel
eluting with 30%
ethyl acetate in hexanes to give the product.
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EXAMPLE 138B
2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione
A mixture of EXAMPLE 138A (1.8 g) and potassium phthalimide (2.356 g) in N,N-
dimethylformamide (30 mL) was heated at 150 C overnight, diluted with ethyl
acetate,
washed with water and brine, dried (MgSO4), filtered, concentrated and
chromatographed on
silica gel eluting with 30% ethyl acetate in hexanes to give the product.
EXAMPLE 138C
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine
A mixture of EXAMPLE 138B (1.4 g) and hydrazine (1.548 mL) in ethanol (40 mL)
was heated at 70 C overnight, cooled to room temperature, slurried with
CH2C12 (200 mL)
and the solid removed by filtration. The filtrate was concentrated and
chromatographed on
silica gel eluting with 100:5:1 ethyl acetate/methanol/NH4OH to give the
product.
EXAMPLE 138D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE 138C (0.266
g), and triethylamine (1.11 mL) in tetrahydrofuran (10 mL) was heated at 70 C
overnight,
diluted with ethyl acetate, washed with water and brine, dried (MgSO4),
filtered, concentrated
and chromatographed on silica gel eluting with 50% ethyl acetate in hexanes to
give the
product.
EXAMPLE 138E
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ R4-fluorotetrahydro-2H-pyran-4-yl)methyll amino } -3 -nitrophenyl)sulfonyll -
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 138D for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.68 (s,
1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.48-7.54 (m,
3H), 7.34 (d, 2H),
7.24 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.70-
3.77 (m, 4H),
3.50-3.55 (m, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.14-2.20 (m, 6H), 1.76-1.84
(m, 4H), 1.38 (t,
2H), 0.92 (s, 6H).
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EXAMPLE 139
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en-1 -yll methyl }
piperazin-1-y1)-N-( { 3-
nitro-4- R1-oxetan-3-ylpiperidin-4-yl)aminolphenyl } sulfony1)-2-(1H-pyrrolo
[2,3 -blpyridin-5 -
yloxy)benzamide
EXAMPLE 139A
tert-butyl 4-(4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoyl)sulfamoy1)-2-
nitrophenylamino)piperidine-1-carboxylate
The title compound was prepared as described in EXAMPLE 53B by replacing 1-
acetylpiperidin-4-amine with 4-amino-piperidine-1-carboxylic acid tert-butyl
ester.
EXAMPLE 139B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-l-y1)-N-(3-nitro-4-(piperidin-4-
ylamino)phenylsulfonyl)benzamide
To a cooled (0 C) solution of EXAMPLE 139A (960 mg) in dichloromethane (10
mL) was added dropwise trifluoroacetic acid (5 mL). The mixture was stirred at
the
temperature for 3 hours. Then, the mixture was concentrated under vacuum and
the residue
was dissolved in dichloromethane (200 mL) and washed with aqueous NaHCO3 and
brine.
After drying over Na2SO4, the mixture was filtered, and evaporation of the
solvent from the
filtrate gave the title compound.
EXAMPLE 139C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R1-oxetan-3-ylpiperidin-4-yl)aminolphenyl } sulfony1)-2-(1H-pyrrolo
[2,3 -blpyridin-5 -
yloxy)benzamide
To a solution of EXAMPLE 139B (120 mg) in tetrahydrofuran (3 mL) and acetic
acid
(1 mL) was added oxetan-3-one (50.8 mg) and MP-cyanoborohydride (2.15 mmol/g,
150
mg). The mixture was stirred at room temperature overnight. The mixture was
filtered. The
filtrate was concentrated and the residue was loaded on a silica gel cartridge
and eluted with
5-10% 7N NH3 in methanol in dichloromethane to give the title compound. 1H NMR
(300
MHz, dimethylsulfoxide-d6) 8 11.62 (s, 1H), 8.51 (d, 1H), 8.20 (d, 1H), 7.99
(d, 1H), 7.74
(m, 1H), 7.48 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.36 (dd,
1H), 6.20 (d, 1H),
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4.54 (t, 2H), 4.43 (t, 2H), 3.66 (m, 1H), 3.44 (m, 3H), 3.04 (m, 5H), 2.73 (s,
2H), 2.61 (m,
2H), 2.12 (m, 11H), 1.61 (m, 2H), 1.38 (t, 2H), 0.93 (m, 6H).
EXAMPLE 140
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-1-
y1)-N-({4-
R1-cyclobutylpiperidin-4-yl)aminol -3 -nitrophenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
oxetan-3-one with cyclobutanone. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8
11.58 (s,
1H), 8.47 (d, 1H), 8.12 (d, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 7.53 (d, 1H),
7.45 (m, 1H), 7.36
(m, 3H), 7.02 (m, 3H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.22 (d, 1H), 3.74 (m,
1H), 2.97 (m, 6H),
2.73 (s, 3H), 2.15 (m, 15H), 1.67 (m, 4H), 1.38 (t, 2H), 0.93 (s, 6H).
EXAMPLE 141
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R4-
{ ll-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yll amino } -3-
nitrophenyl)sulfonyll -2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
oxetan-3-one with 2,2-dimethyltetrahydropyran-4-one. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.60 (s, 1H), 8.50 (d, 1H), 8.15 (m, 1H), 7.99 (d,
1H), 7.78 (m,
1H), 7.62 (m, 1H), 7.47 (m, 3H), 7.34 (m, 3H), 7.05 (m, 3H), 6.65 (m, 2H),
6.35 (dd, 1H),
6.21 (d, 1H), 4.56 (d, 3H), 3.89 (m, 3H), 3.67 (m, 6H), 3.45 (m, 2H), 3.04 (m,
3H), 2.75 (m,
3H), 2.14 (m, 3H), 1.71 (m, 5H), 1.16 (s, 9H).
EXAMPLE 142
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-l-
y1)-N- R4-
{ R3S)-1-cyclopropylpyrrolidin-3-y11amino } -3 -nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 142A
(S)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate
(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg), (1-
ethoxycyclopropoxy)trimethylsilane (1.8 mL) and molecular sieves (500 mg) were
combined
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in methanol (4.5 mL). Acetic acid (1.3 mL) was added, followed by sodium
cyanoborohydride (420 mg). The resulting mixture was heated to reflux for 4
hours.
Insoluble material was filtered off and reaction was made basic to pH 14 with
addition of 6M
aqueous NaOH solution. The solution was extracted three times with diethyl
ether, and the
combined extracts were dried over MgSO4, filtered and concentrated to obtain
an oil, which
was purified by flash chromatography, eluting first with 100% dichloromethane,
followed by
5% methanol/dichloromethane and 10% methanol/dichloromethane.
EXAMPLE 142B
(S)-1-cyclopropylpyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 142A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 142C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
111(35)-1-cyclopropylpyrrolidin-3-y11aminol-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 142B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
11.64 (s, 1H), 8.51 (m, 2H), 8.30 (m, 1H), 8.00 (br s, 1H), 7.77 (m, 1H), 7.49
(m, 3H), 7.34
(d, 2H), 7.04 (d, 2H), 6.97 (br s, 1H), 6.67 (dd, 1H), 6.36 (m, 1H), 6.21 (m,
1H), 4.19 (m,
1H), 3.00 (m, 5H), 2.74 (m, 3H), 2.64 (m, 1H), 2.36 (m, 1H), 2.15 (m, 6H),
1.95 (s, 2H), 1.78
(br s, 1H), 1.68 (m, 1H), 1.38 (t, 2H), 1.23 (m, 1H), 0.92 (s, 6H), 0.39 (m,
4H).
EXAMPLE 143
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
nitro-4- R1-tetrahydrofuran-3-ylpiperidin-4-yl)aminolphenyllsulfonyl)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
oxetan-3-one with 3-oxotetrahydrofuran. 1H NMR (300 MHz, dimethylsulfoxide-d6)
8 11.65
(s, 1H), 8.53 (d, 1H), 8.21 (m, 1H), 8.02 (m, 1H), 7.80 (dd, 1H), 7.49 (m,
3H), 7.34 (m, 3H),
7.05 (m, 3H), 6.67 (dd, 1H), 6.37 (m, 1H), 6.19 (d, 1H), 4.29 (m, 3H), 3.73
(m, 6H), 3.09 (m,
4H), 2.76 (m, 2H), 2.05 (m, 8H), 1.68 (m, 2H), 1.37 (m, 2H), 0.94 (s, 6H).
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EXAMPLE 144
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-cyclopropylpyrrolidin-3-yllaminol-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 144A
(R)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylcarbamate for (S)-tert-butyl pyrrolidin-3-ylcarbamate in EXAMPLE 142A.
EXAMPLE 144B
(R)-1-cyclopropylpyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 144A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 144C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-cyclopropylpyrrolidin-3-yllaminol-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 144B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
11.66 (s, 1H), 8.53 (d, 2H), 8.32 (d, 1H), 8.02 (d, 1H), 7.81 (m, 1H), 7.49
(m, 3H), 7.34 (d,
2H), 7.03 (m, 3H), 6.67 (dd, 1H), 6.37 (m, 1H), 6.20 (d, 1H), 4.21 (m, 1H),
3.00 (m, 5H),
2.74 (m, 3H), 2.64 (m, 1H), 2.36 (m, 1H), 2.15 (m, 6H), 1.95 (s, 2H), 1.74 (br
s, 1H), 1.66
(m, 1H), 1.38 (t, 2H), 1.23 (m, 1H), 0.92 (s, 6H), 0.39 (m, 4H).
EXAMPLE 145
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-113-
nitro-4-(11(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-
yllmethyllamino)phenyllsulfonyll-
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
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EXAMPLE 145A
(S)-tert-butyl (1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylmethylcarbamate for tert-butyl piperazine-l-carboxylate and dihydro-2H-pyran-
4(3H)-one
for 4'-chlorobipheny1-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 145B
(S)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine
The title compound was prepared by substituting EXAMPLE 145A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 145C
(S)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-l-y1)-N-(3-nitro-44(1-(tetrahydro-2H-pyran-4-
yl)pyrrolidin-3-
yl)methylamino)phenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 145B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (500MHz, dimethylsulfoxide-d6)
8
11.58 (s, 1H), 8.61 (br s, 1H), 8.46 (s, 1H), 7.96 (d, 1H), 7.72 (m, 1H), 7.54
(d, 1H), 7.45 (t,
1H), 7.37 (br s, 2H),7.34 (d, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.64 (dd, 1H),
6.34 (m, 1H),
6.22 (d, 1H), 3.89 (m, 2H), 3.38 (m, 4H), 3.27 (m, 4H), 3.02 (m, 5H), 2.73 (s,
2H), 2.61 (m,
1H), 2.18 (m, 6H), 2.05 (m, 1H), 1.95 (m, 2H), 1.85 (m, 2H), 1.64 (m, 1H),
1.50 (m, 2H),
1.38 (m, 2H), 0.94 (s, 6H).
EXAMPLE 146
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 4-
R3-hydroxy-2,2-dimethylpropyl)aminol -3-nitrophenyl } sulfony0-2-(1H-pyrrolo
[2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 120B using 3-amino-
2,2-dimethylpropan-1-ol in place of EXAMPLE 120A. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 8 11.68 (s, 1H), 11.35 (s, 1H), 8.96 (t, 1H), 8.56 (d,
1H), 8.05 (d, 1H),
7.79 (dd, 1H), 7.46 - 7.56 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H),
6.39 (dd, 1H), 6.19 (d, 1H), 5.10 (t, 1H), 3.29 (d, 1H), 3.24 (d, 1H), 3.07
(s, 4H), 2.75 (s, 2H),
2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93 (d, 12H).
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EXAMPLE 147
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yl[methyl}piperazin-
1-y1)-N- { [4-
( { 111-(methylsulfonyl)piperidin-3 -yl[methyl}amino)-3-nitrophenyl[sulfonyll-
2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 147A
tert-butyl (1-(methylsulfonyl)piperidin-3-yl)methylcarbamate
tert-Butyl piperidin-3-ylmethylcarbamate(500 mg) was dissolved in anhydrous
dichloromethane (10 mL), and methanesulfonyl chloride (0.181 mL) was added
followed by
the addition of triethylamine (1.3 mL). The reaction mixture was stirred at
room temperature
overnight. The organic solvent was removed under vacuum. The residue was
purified with
flash column chromatography on silica gel eluting with 0-70% ethyl acetate in
hexane to give
the title compound.
EXAMPLE 147B
(1-(methylsulfonyl)piperidin-3-yl)methanamine
EXAMPLE 147A (400 mg) was suspended in 4N HC1 in dioxane (10 mL) followed
by the addition of anhydrous methanol (1 mL). The clear solution was stirred
at room
temperature for 2 hours. The organic solvent was removed under vacuum. The
solid residue
was used in the next step without further purification.
EXAMPLE 147C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yl[methyl}piperazin-1-
y1)-N- { 114-
( { [1-(methylsulfonyl)piperidin-3-Amethyl}amino)-3-nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 53A (50 mg), EXAMPLE 147B (26 mg) and triethylamine (0.088 mL)
were dissolved in anhydrous dioxane (1mL) and N,N-dimethylformamide (0.2 mL).
The
reaction vial was heated in a Biotage Initiator microwave reactor at 130 C for
25 minutes.
The solvent was removed under vacuum. The residue was purified by reverse
phase HPLC
on a C18 column using a gradient of 20-80% acetonitrile/0.1% trifluoroacetic
acid in water to
give the title compound as the trifluoroacetate salt. The trifluoroacetic acid
salt was
dissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO3. The
organic
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layer was dried over anhydrous Na2SO4 and concentrated to give the title
compound. 1H
NMR (400MHz, dimethylsulfoxide-d6) 8 11.65 (s, 1H), 8.56 (m, 2H), 8.03 (d,
1H), 7.80 (m,
1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H),
6.38 (dd, 1H),
6.19 (d, 1H), 3.52 (m, 1H), 3.40 (m, 2H), 3.06 (m, 4H), 2.84 (s, 3H), 2.75 (m,
2H), 2.75 (m,
4H), 2.58 (m, 1H), 2.16 (m, 6H), 1.95 (s, 3H), 1.76 (m, 2H), 1.52 (m, 1H),
1.37 (m, 2H), 0.92
(s, 6H).
EXAMPLE 148
N- 11(4- { R1- acetylpiperidin-3 -yl)methyll amino } -3-nitrophenyl)sulfonyll-
4-(4- { 11244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 148A
tert-butyl (1-acetylpiperidin-3-yl)methylcarbamate
The title compound was prepared by substituting acetyl chloride for
methanesulfonyl
chloride in EXAMPLE 147A.
EXAMPLE 148B
1-(3-(aminomethyl)piperidin-1-yl)ethanone
The title compound was prepared by substituting EXAMPLE 148A for EXAMPLE
147A in EXAMPLE 147B.
EXAMPLE 148C
N- 11(4- { R1- acetylpiperidin-3 -yl)methyll amino } -3-nitrophenyl)sulfonyll-
4-(4- { 11244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 148B for EXAMPLE
147B in EXAMPLE 147C. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.56
(m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.12 (m, 1H),
7.04 (d, 2H),
6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37
(m, 2H), 3.24 (m,
2H), 3.07 (m, 4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s, 3H),
1.80 (m, 4H), 1.38
(t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).
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EXAMPLE 149
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-(methylsulfonyl)pyrrolidin-3-yll amino1-3-nitrophenyl)sulfonyll-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 149A
(R)-tert-butyl 1-(methylsulfonyl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate in EXAMPLE 147A.
EXAMPLE 149B
(R)-1-(methylsulfonyl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 149A for EXAMPLE
147A in EXAMPLE 147B.
EXAMPLE 149C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-(methylsulfonyl)pyrrolidin-3-yll amino1-3-nitrophenyl)sulfonyll -2-
(1H-pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 149B for EXAMPLE
147B in EXAMPLE 147C. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.65 (s, 1H),
8.55
(d, 1H), 8.29 (d, 1H), 8.02 (d, 1H), 7.86 (dd, 1H), 7.49 (m, 3H), 7.33 (d,
2H), 7.17 (d, 1H),
7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.41 (m, 1H), 3.69
(m, 1H), 3.39 (m,
3H), 3.06 (m, 4H), 2.97 (s, 3H), 2.76 (m, 2H), 2.27 (m, 8H), 1.93 (m, 2H),
1.54 (m, 1H), 1.38
(t, 2H), 0.92 (s, 6H).
EXAMPLE 150
4-(4-112-(4-chloropheny1)-3,3 -dimethylcyclohex-1-en-l-yll methyllpiperazin-1-
y1)-N-(13-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 150A
Ethyl 2-hydroxy-3,3-dimethylcyclohex-1-enecarboxylate
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Into a 500 mL round-bottomed flask was added diisopropylamine (3.5 mL) in
ether
(200 mL). After cooling to -30 C, butyllithium (16 mL) (1.6M in hexane) was
added slowly.
After stirring 30 minutes, the temperature was cooled to -5 C. 2,2-
Dimethylcyclohexanone
(3 g) was added slowly. The mixture was warmed up to 0 C and stirred for 1
hour. After
cooling to -5 C, hexamethylphosphoramide (8 mL) and ethyl carbonocyanidate
(2.5 mL)
were added. After stirring at -5 C for 20 minutes, and warming to room
temperature, the
reaction was stirred for 1 hour. The mixture was poured into cold water, and
the layers were
separated. The aqueous layer was extracted with ether (3x 20 mL). The combined
the organic
layers were washed with saturated aqueous NH4C1 (3x 20 mL). After drying over
Na2SO4, the
mixture was filtered and the filtrate was concentrated. The crude product was
purified by
flash chromatography on silica with 0-10% ethyl acetate in hexanes to provide
the title
compound.
EXAMPLE 150B
Ethyl 3,3-dimethy1-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
The title compound was prepared by substituting EXAMPLE 150A for EXAMPLE
101A in EXAMPLE 101B.
EXAMPLE 150C
Ethyl 2-(4-chloropheny1)-3,3-dimethylcyclohex-1-enecarboxylate
The title compound was prepared by substituting EXAMPLE 150B for EXAMPLE
101B in EXAMPLE 101C.
EXAMPLE 150D
(2-(4-chloropheny1)-3,3-dimethylcyclohex-1-enyl)methanol
In a 200 mL round-bottomed flask was added EXAMPLE 150C (0.97 g) and lithium
borohydride (0.47 g) in ether (20 mL) to give a suspension. Methanol (2.2 mL)
was added
slowly. The mixture was refluxed overnight. The reaction was then cooled, and
methanol was
added to quench the reaction. 1N aqueous HC1 was then added until the pH<7,
and ether (3x
mL) was used to extract the product. The combined organic layers were dried
over
30 Na2SO4, filtered, and concentrated. The crude material was purified by
flash chromatography
on silica with 0-25% ethyl acetate in hexanes to provide the title compound.
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EXAMPLE 150E
2-(4-chloropheny1)-3,3-dimethylcyclohex-1-enecarbaldehyde
Into a 100 mL round-bottomed flask was added EXAMPLE 150D (0.3 g) and Dess-
Martin Periodinane (0.6 g) in dichloromethane (10 mL) to give a suspension.
The mixture
was stirred at room temperature overnight. After filtration, the mixture was
washed with
saturated aqueous NaHCO3 (2x 20 mL), dried over Na2SO4, filtered, and
concentrated. The
crude product was purified by flash chromatography on silica with 0-25% ethyl
acetate in
hexanes to provide the title compound.
EXAMPLE 150F
Methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-3,3-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoate
The title compound was prepared by substituting EXAMPLE 150E for 4'-
chlorobipheny1-2-carboxaldehyde and EXAMPLE 15F for tert-butyl piperazine-1-
carboxylate in EXAMPLE 1A.
EXAMPLE 150G
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-3,3-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 150F for EXAMPLE
101E in EXAMPLE 101F.
EXAMPLE 150H
4-(4- { [2-(4-chloropheny1)-3,3-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N4 { 3-
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl}sulfony1)-2-(1H-pyrrolo
1L2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 150G for EXAMPLE 3J
and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethyl
sulfoxide-d6) 6 11.50 (s, 1H), 8.36 (m, 1H), 8.32 (m, 1H), 7.91 (d, 1H), 7.59
(m, 2H), 7.40 (t,
1H), 7.35 (d, 2H), 7.25 (m, 1H), 6.94 (d, 2H), 6.79 (d, 1H), 6.60 (m, 1H),
6.29 (m, 1H), 6.24
(d, 1H), 3.83 (m, 2H), 3.25 (m, 4H), 2.98 (m, 4H), 2.42 (s, 2H), 2.14 (m, 6H),
1.60 (m, 6H),
1.25 (m, 3H), 0.86 (s, 6H)
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EXAMPLE 151
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yflmethyl}piperazin-1-
y1)-N- { [4-
( { 1- [2-fluoro-1-(fluoromethyBethyflazetidin-3-yl}amino)-3-
nitrophenyl[sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 151A
1-(1,3-difluoropropan-2-yl)azetidin-3-amine
To a solution of tert-butyl azetidin-3-ylcarbamate (0.256 g) and 1,3-
difluoropropan-2-
one (0.154 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride
(0.473 g)
and the reaction was allowed to stirred at room temperature. After 16 hours,
the reaction was
quenched with saturated NaHCO3 solution (10 mL) and extracted into
dichloromethane (25
mL). The organic layer was dried and concentrated. Silica gel chromatography
(GraceResolv 12 g) eluting with a gradient of 0.5% to 3.5%
methanol/dichloromethane
followed by treatment with HC1 (4.0M in dioxane, 3 mL) and methanol (0.5 mL)
for 2 hours
gave the title compound after concentration.
EXAMPLE 151B
4-(1-(1,3-difluoropropan-2-yl)azetidin-3-ylamino)-3-nitrobenzenesulfonamide
To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225 g) and 1-(1,3-
difluoropropan-2-yl)azetidin-3-amine (0.193 g) in dioxane (5 mL) was added
diisopropylamine (0.832 mL). The reaction was sonicated and then heated to 100
C. After
stirring overnight, the reaction was concentrated and loaded onto silica gel
(GraceResolv 12
g) and eluted with a gradient of 0.5% to 3.5% methanol/dichloromethane to give
the title
compound.
EXAMPLE 151C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 1- [2-fluoro-1-(fluoromethyBethyl] azetidin-3-yl}amino)-3-nitrophenyfl
sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 151B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.66 (s, 1H), 11.54 - 11.28 (m, 1H), 8.54 (d, 1H),
8.45 (s, 1H), 8.01
(d, 1H), 7.82 (d, 1H), 7.48 (d, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.90 (d, 1H),
6.67 (d, 1H), 6.37
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(s, 1H), 6.20 (s, 1H), 4.64 - 4.23 (m, 6H), 3.81 (s, 2H), 3.08 (s, 4H), 2.75
(s, 3H), 2.15 (s,
7H), 1.95 (s, 2H), 1.38 (s, 2H), 0.92 (s, 6H).
EXAMPLE 152
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { [1-(methylsulfonyl)pyrrolidin-3-yl[methyl}amino)-3-nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 152A
tert-butyl (1-(methylsulfonyl)pyrrolidin-3-yl)methylcarbamate
The title compound was prepared by substituting tert-butyl pyrrolidin-3-
ylmethylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate in EXAMPLE
147A.
EXAMPLE 152B
(1-(methylsulfonyl)pyrrolidin-3-yl)methanamine
The title compound was prepared by substituting EXAMPLE 152A for EXAMPLE
147A in EXAMPLE 147B.
EXAMPLE 152C
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { [1-(methylsulfonyl)pyrrolidin-3-yl[methyl}amino)-3-nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 152B for EXAMPLE
147B in EXAMPLE 147C. 1H NMR (400MHz, dimethylsulfoxide-d6) 811.60 (s, 1H),
8.49
(m, 2H), 7.99 (s, 1H), 7.73 (m, 1H), 7.53 (d, 1H), 7.47 (s, 1H), 7.42 (m, 1H),
7.34 (d, 2H),
7.04 (m, 3H), 6.65 (m, 1H), 6.35 (s, 1H), 6.22 (s, 1H), 3.41 (m, 4H), 3.22 (m,
2H), 3.03 (m,
4H), 2.89 (s, 3H), 2.73 (m, 2H), 2.59 (m, 1H), 2.17 (m, 6H), 2.00 (m, 4H),
1.68 (m, 1H), 1.38
(t, 2H), 0.92 (s, 6H).
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EXAMPLE 153
N- [(4- { [(1-acetylpyrrolidin-3-yl)methyl[amino}-3-nitrophenyl)sulfonyll-4-(4-
{ [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo 112,3 -
b[pyridin-5-yloxy)benzamide
EXAMPLE 153A
tert-butyl (1-acetylpyrrolidin-3-yl)methylcarbamate
The title compound was prepared by substituting tert-butyl pyrrolidin-3-
ylmethylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl
chloride for
methanesulfonyl chloride in EXAMPLE 147A.
EXAMPLE 153B
1-(3-(aminomethyl)pyrrolidin-1-yl)ethanone
The title compound was prepared by substituting EXAMPLE 153A for EXAMPLE
147A in EXAMPLE 147B.
EXAMPLE 153C
N- [(4- { [(1-acetylpyrrolidin-3-yl)methyl[amino}-3-nitrophenyl)sulfonyll-4-(4-
{ [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo 112,3 -
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 153B for EXAMPLE
147B in EXAMPLE 147C. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.66 (s, 1H),
8.62
(m, 1H), 8.54 (s, 1H), 8.03 (m, 1H), 7.78 (d, 1H), 7.50 (m, 3H), 7.35 (t, 2H),
7.09 (s, 1H),
7.04 (d, 2H), 6.67 (dd, 1H), 6.37 (d, 1H), 6.20 (s, 1H), 3.56 (m, 1H), 3.42
(m, 4H), 3.43 (m,
4H), 3.23 (m, 1H), 3.07 (m, 4H), 2.74 (m, 2H), 2.16 (m, 6H), 1.93 (m, 5H),
1.38 (t, 2H), 0.93
(s, 6H).
EXAMPLE 154
N- [(4- { R3R)-1-acetylpyrrolidin-3-yl[amino}-3-nitrophenyl)sulfonyll-4-(4- {
[2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo 112,3 -
b[pyridin-5-yloxy)benzamide
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EXAMPLE 154A
(R)-tert-butyl 1-acetylpyrrolidin-3-ylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl chloride
for
methanesulfonyl chloride in EXAMPLE 147A.
EXAMPLE 154B
(R)-1-(3-aminopyrrolidin-l-yl)ethanone
The title compound was prepared by substituting EXAMPLE 154A for EXAMPLE
147A in EXAMPLE 147B.
EXAMPLE 154C
N- 11(4- { R3R)-1-acetylpyrrolidin-3-yll amino } -3 -nitrophenyl)sulfonyll -4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 154B for EXAMPLE
147B in EXAMPLE 147. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.61 (s, 1H),
8.50 (s,
1H), 8.17 (d, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.49 (m, 3H), 7.34 (d, 2H),
7.10 (m, 1H), 7.04
(d, 2H), 6.66 (dd, 1H), 6.35 (s, 1H), 6.22 (s, 1H), 4.34 (m, 1H), 3.81 (m,
1H), 3.58 (m, 1H),
3.43 (m, 1H), 3.05 (m, 4H), 2.74 (s, 2H), 2.19 (m, 9H), 1.96 (m, 5H), 1.38 (t,
2H), 0.94 (s,
6H).
EXAMPLE 155
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R3-methoxy-2,2-dimethylpropyl)aminol-3-nitrophenyl I sulfony1)-2-(1H-pyrrolo
112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 120B using 3-methoxy-
2,2-dimethylpropan-1-amine in place of EXAMPLE 120A. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.32 (s, 1H), 8.92 (t, 1H), 8.57 (d,
1H), 8.04 (d, 1H),
7.80 (dd, 1H), 7.46 - 7.55 (m, 3H), 7.34 (d, 2H), 7.08 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H),
6.36 - 6.42 (m, 1H), 6.19 (d, 1H), 3.25 - 3.30 (m, 5H), 3.19 (s, 2H), 3.07 (s,
4H), 2.76 (s, 2H),
2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.96 (s, 6H), 0.92 (s, 6H).
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EXAMPLE 156
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(1 R1R,3R)-3-hydroxyc yclopentyll methyl I amino)-3-nitrophenyll sulfonyl I -2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 156A
4-(((1R,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (1R,3R)-3-
hydroxycyclopentyl)methylamine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
EXAMPLE 156B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(1 R1R,3R)-3-hydroxyc yclopentyll methyl I amino)-3-nitrophenyll sulfonyl I -2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 156A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.05 (s, 1H), 9.29 (s,
1H),
8.62 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.85 (d, 1H), 6.74 (dd, 1H), 6.54 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H),
3.19 (dd, 2H), 3.06
(m, 4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H), 2.00 (m,
1H), 1.97 (s,
2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t, 2H), 1.34 (m, 1H), 0.93 (s, 6H).
EXAMPLE 157
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ R1S ,3S)-3-hydroxycyclopentyll methyl } amino)-3-nitrophenyllsulfonyl I -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMLE 157A
4-(((1S,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (1S, 3S)-3-
hydroxycyclopentyl)methylamine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
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EXAMPLE 157B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { R1S,3S)-3-hydroxycyclopentyl[methyl}amino)-3-nitrophenyl[sulfonyll-2-(1H-
pyrrolo [2,3 -
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 157A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.03 (s, 1H), 9.29 (s,
1H),
8.60 (t, 1H), 8.44 (d, 1H), 8.32 (dd, 1H), 8.14 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.55 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H),
3.19 (dd, 2H), 3.06
(m, 4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H), 2.00 (m,
1H), 1.97 (s,
2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t, 2H), 1.34 (m, 1H), 0.93 (s, 6H).
EXAMPLE 158
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { R1S ,3R)-3 -hydroxycyclopentyl[methyl}amino)-3 -nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 158A
4-(((1S,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (1S, 3R)-3-
hydroxycyclopentyl)methylamine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
EXAMPLE 158B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { R1S ,3R)-3 -hydroxycyclopentyl[methyl}amino)-3 -nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 158A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 12.94 (s, 1H), 9.25 (d,
1H),
8.59 (t, 1H), 8.48 (d, 1H), 8.27 (m, 2H), 7.66 (m, 2H), 7.45 (d, 2H), 7.08 (d,
2H), 6.77 (dd,
1H), 6.72 (d, 1H), 6.60 (d, 1H), 6.47 (m, 1H), 4.53 (m, 1H), 3.30 (m, 2H),
3.06 (m, 4H), 2.78
(s, 2H), 2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.98 (m, 3H), 1.85-1.66 (m, 4H),
1.39 (t, 2H), 0.94
(s, 6H).
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EXAMPLE 159
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { R1R,3S)-3-hydroxycyclopentyl[methyl}amino)-3-nitrophenyllsulfonyll-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 159A
4-(((1R,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (1R, 3S)-3-
hydroxycyclopentyl)methylamine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
EXAMPLE 159B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { R1R,3S)-3-hydroxycyclopentyl[methyl}amino)-3-nitrophenyllsulfonyll-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 158A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.02 (s, 1H), 9.28 (d,
1H),
8.59 (t, 1H), 8.44 (d, 1H), 8.29 (d, 1H), 8.13 (d, 1H), 7.66 (m, 2H), 7.44 (d,
2H), 7.08 (d, 2H),
6.82 (dd, 1H), 6.74 (d, 1H), 6.55 (d, 1H), 6.48 (m, 1H), 4.53 (m, 1H), 3.34
(m, 2H), 3.06 (m,
4H), 2.77 (s, 2H), 2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.97 (m, 3H), 1.85-1.66
(m, 4H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 160
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(3 -
nitro-4- { R35)-2-oxopiperidin-3-yl[amino}phenyl)sulfony11-2-(1H-pyrrolo[2,3-
b[pyridin-5-
yloxy)benzamide
The title compound was prepared by substituting (S)-3-aminopiperidin-2-one for
1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz, dimethylsulfoxide-d6)
8
11.68 (br s, 1H), 8.88 (d, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.95 (br s, 1H),
7.83 (dd, 1H), 7.55-
7.46 (m, 3H), 7.35 (d, 2H), 7.16 (d, 1H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.38
(m, 1H), 6.21 (d,
1H), 4.41 (m, 1H), 3.22 (m, 2H), 3.09 (br s, 4H), 2.78 (br s, 2H), 2.35-2.09
(m, 8H), 1.96 (br
s, 2H), 1.86 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 161
4- (4-112-(4-chloropheny1)-4,4-dimethylcyclohex-l-en-1 -yll methyllpiperazin-1-
y1)-N-(14-
1(11-12-fluoro-1-(fluoromethyBethyll azetidin-3-yllmethyl)aminol -3 -
nitrophenyllsulfony1)-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 161A
tert-butyl 3-((4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoyl)sulfamoy1)-2-
nitrophenylamino)methyBazetidine-1-carboxylate
EXAMPLE 82 (305 mg). tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (86 mg)
and diisopropyl amine (0.202 mL) in dioxane (3 mL) were heated to 110 C. After
stirring
overnight, the reaction was concentrated. Silica gel chromatography
(Reveleris, 12 g) eluting
with a gradient of 0.5% to 3% methanol/dichloromethane (Flow = 36 ml/minute)
gave the
title compound.
EXAMPLE 161B
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-N-(4-(azetidin-3-ylmethylamino)-3-
nitrophenylsulfony1)-4-(44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzamide
To a solution of EXAMPLE 161A (0.257 g) in dichloromethane (5 mL) was added
trifluoroacetic acid (0.211 mL), After 30 minutes an additional 0.2 ml of
trifluoroacetic acid
was added. After 3 hours, the reaction was concentrated to give the title
compound.
EXAMPLE 161C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(11-12-fluoro-1-(fluoromethyBethyll azetidin-3-yllmethyl)aminol -3 -
nitrophenyllsulfony1)-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
A solution of EXAMPLE 161B (0.118 g), sodium triacetoxyborohydride (0.035 g)
and 1,3-difluoropropan-2-one (0.012 g) were stirred together in
dichloromethane (1 mL)
overnight. The reaction was quenched with saturated aqueous NaHCO3 solution
(10 mL) and
extracted into dichloromethane (30 mL). The organic layer was dried and
concentrated.
Silica gel chromatography (Reveleris 12 g) eluting with a gradient of 0.5% to
3.5%
methanol/dichloromethane over 30 minutes (Flow = 36 ml/min) gave the title
compound. 1H
NMR (300 MHz, dimethylsulfoxide-d6) 6 11.67 (s, 1H), 11.47 - 11.21 (m, 1H),
8.85 (s, 1H),
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8.55 (d, 1H), 8.03 (d, 1H), 7.80 (dd, 1H), 7.54 - 7.45 (m, 3H), 7.33 (s, 2H),
7.04 (d, 3H), 6.67
(d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.43 (dt, 4H), 3.56 (t, 2H), 3.46 (s,
2H), 3.12 (m, 6H),
2.74 (m, 3H), 2.17 (m, 7H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).
EXAMPLE 162
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { R1-oxetan-3-ylazetidin-3-yl)methyll amino } phenyl)sulfonyll -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting oxetan-3-one for 1,3-
difluoropropan-2-one in EXAMPLE 161C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 6

11.66 (s, 1H), 11.51 - 11.03 (m, 1H), 8.81 (s, 1H), 8.54 (d, 1H), 8.02 (d,
1H), 7.79 (dd, 1H),
7.50 (dd, 3H), 7.34 (d, 2H), 7.04 (d, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20
(d, 1H), 4.57 (s,
2H), 4.43 - 4.35 (m, 2H), 3.82 (s, 1H), 3.59 (t, 2H), 3.44 (t, 2H), 3.20 (s,
2H), 3.06 (s, 4H),
2.73 (s, 3H), 2.18 (s, 6H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).
EXAMPLE 163
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { R1-oxetan-3-ylpiperidin-4-yl)methyll amino } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 163A
tert-butyl 4-((4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoyl)sulfamoy1)-2-
nitrophenylamino)methyl)piperidine-1-carboxylate
The title compound was prepared by substituting tert-butyl 4-
(aminomethyl)piperidine-1-carboxylate for 1-acetylpiperidin-4-amine in EXAMPLE
53B.
EXAMPLE 163B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-l-y1)-N-(3-nitro-4-(piperidin-4-
ylmethylamino)phenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 163A for EXAMPLE
1A in EXAMPLE 1B.
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EXAMPLE 163C
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyc lohex-1 -en-1 -yll methyl }
piperazin- 1 -y1)-N- R3 -
nitro-4- { [(1-oxetan-3-ylpiperidin-4-yl)methyll amino } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
bl pyridin-5 -yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 163B for EXAMPLE
161B and oxetan-3-one for 1,3-difluoropropan-2-one in EXAMPLE 161C. 1H NMR
(500MHz, dimethylsulfoxide-d6) 8 11.68 (s, 1H), 8.60 (t, 1H), 8.54 (d, 1H),
8.03 (d, 1H),
7.79 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.67
(dd, 1H), 6.39 (m,
1H), 6.19 (d, 1H), 4.55 (t, 2H), 4.46 (t, 2H), 3.52 (br s, 1H), 3.28 (m, 2H),
3.17 (d, 1H), 3.06
(m, 4H), 2.82 (m, 2H), 2.74 (m, 2H), 2.17 (m, 6H), 1.95 (m, 3H), 1.72 (m, 3H),
1.38 (t, 2H),
1.28 (m, 2H), 0.92 (s, 6H).
EXAMPLE 164
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyc lohex-1 -en-1 -yll methyl }
piperazin- 1 -y1)-N- l(4-
{ R1 -cyc lopropylpiperidin-4-yl)methyll amino } -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5 -yloxy)benzamide
The title compound was prepared by substituting EXMAPLE 163B for (S)-tert-
butyl
pyrrolidin-3-ylcarbamate in EXAMPLE 142A. 1H NMR (500MHz, dimethylsulfoxide-
d6) 8
11.96 (br s, 1H), 11.62 (br s, 1H), 8.50 (m, 2H), 7.98 (d, 1H), 7.72 (m, 1H),
7.52 (d, 1H), 7.45
(m, 2H), 7.34 (d, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.64 (dd, 1H), 6.34 (m,
1H), 6.22 (d, 1H),
3.28 (m, 3H), 3.04 (m, 5H), 2.72 (s, 2H), 2.64 (m, 1H), 2.64 (m, 1H), 2.36 (m,
1H), 2.16 (m,
7H), 1.95 (s, 2H), 1.68 (m, 3H), 1.38 (t, 2H), 1.18 (m, 3H), 0.94 (s, 6H),
0.35 (m, 3H).
EXAMPLE 165
4-(4- { l2-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en-1 -yll methyl }
piperazin- 1-y1)-N- { [4-
({ [4-(2-fluoroethyl)morpholin-2-yll methyl } amino)-3-nitrophenyllsulfonyl I -
2-(1H-
pyrrolo [2,3 -bl pyridin-5-yloxy)benzamide
EXAMPLE 165A
4-((4-(2-fluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 2-fluoro-ethyl bromide for
methyl
iodide in EXAMPLE 134B.
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EXAMPLE 165B
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ 1L4-(2-fluoroethyl)morpholin-2-yll methyl } amino)-3-nitrophenyllsulfonyl I
-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 165A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.26 (d,
1H),
8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.92 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 3.93 (m, 1H),
4.63, 4.51(dt,
2H), 3.95-3.85 (m, 2H), 3.68 (dt, 1H), 3.43-3.37 (m, 2H), 3.07 (m, 4H), 2.92
(d, 1H), 2.77 (s,
2H), 2.65 (m, 2H), 2.59 (m, 1H), 2.26 (m, 2H), 2.17-2.08 (m, 5H), 1.97 (s,
2H), 1.39 (t, 2H),
0.93 (s, 6H).
EXAMPLE 166
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ [4-(2,2-difluoroethyl)morpholin-2-yll methyl } amino)-3-
nitrophenyllsulfonyl I -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 166A
4-((4-(2,2-difluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2,2-difluoro-ethyl bromide for
methyl iodide in EXAMPLE 134B.
EXAMPLE 166B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ [4-(2,2-difluoroethyl)morpholin-2-yll methyl } amino)-3-
nitrophenyllsulfonyl I -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 166A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.01 (s, 1H), 9.26 (d,
1H),
8.86 (t, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.93 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 6.31, 6.20, 6.09
(tt, 1H), 3.90
(m, 1H), 3.85 (d, 1H), 3.67 (dt, 1H), 3.49-3.30 (m, 2H), 3.07 (m, 4H), 2.84
(d, 1H), 2.82-2.75
(m, 4H), 2.69 (d, 1H), 2.33 (dt, 1H), 2.27-2.20 (m, 3H), 2.14 (m, 4H), 1.97
(s, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
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EXAMPLE 167
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 4-
R4-fluoro-1-oxetan-3 -ylpiperidin-4-yl)methoxyl -3 -nitrophenyl } sulfony1)-2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 167A
4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 173A for tert-butyl
piperazine-l-carboxylate and 3-oxetanone for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A.
EXAMPLE 167B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluoro-1-oxetan-3 -ylpiperidin-4-yl)methoxyl -3 -nitrophenyl } sulfony1)-2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 167A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H),
8.39 (s,
1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.52 (m, 4H), 7.35 (d, 2H), 7.05 (m, 2H),
6.68 (dd, 1H), 6.40
(dd, 1H), 6.20 (s, 1H), 4.57 (t, 2H), 4.48 (m, 2H), 4.38 (d, 2H), 4.02 (m,
1H), 3.63 (m, 2H),
3.08 (m, 4H), 2.74 (m, 4H), 2.17 (m, 6H), 1.88 (m, 6H), 1.40 (t, 2H), 0.93 (s,
6H).
EXAMPLE 168
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f R2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yllmethoxy I -3 -
nitrophenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 168A
(S)-methyl 4,4-difluoropyrrolidine-2-carboxylate
(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (0.472 g)
in
CH2C12 (1 mL) was treated with trifluoroacetic acid (1.4 mL), stirred at
ambient temperature
for 4 hours, and concentrated. The product was free-based using a MEGA BE-SCX
column
with 1:1 CH2C12/methanol as eluent for the trifluoroacetic acid. The product
was released
from the column with 5% (7 M ammonia in methanol) in CH2C12 as eluent.
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EXAMPLE 168B
(S)-methyl 4,4-difluoro-1-(oxetan-3-yl)pyrrolidine-2-carboxylate
The title compound was prepared by substituting EXAMPLE 168A for tert-butyl
piperazine-l-carboxylate and 3-oxetanone for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A.
EXAMPLE 168C
(S)-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methanol
EXAMPLE 168B (0.180 g) in tetrahydrofuran (3 mL) was treated sequentially with
a
solution of calcium chloride (0.245 g) in ethanol (3 mL) and NaBH4 (0.167 g)
and then
stirred at ambient temperature for 7 hours. The reaction was quenched with
saturated
aqueous NH4C1 solution and extracted with ethyl acetate. The combined extracts
were
washed with brine, dried (MgSO4), filtered, concentrated and chromatographed
on silica gel
with 50% ethyl acetate in hexanes as eluent to give the product.
EXAMPLE 168D
(S)-4-((4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methoxy)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 168C for (tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 168E
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R25)-4,4-difluoro-1-oxetan-3 -ylpyrrolidin-2-yll methoxy I -3 -
nitrophenyl)sulfonyll -2-(1H-
pyrrolo112,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 168D for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H),
8.38 (s,
1H), 8.06 (m, 2H), 7.49 (m, 4H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H),
6.40 (m, 1H), 6.21
(s, 1H), 4.54 (m, 3H), 4.43 (t, 1H), 4.23 (m, 1H), 4.12 (m, 2H), 3.44 (m, 2H),
3.12 (m, 7H),
2.58 (m, 1H), 2.29 (m, 7H), 1.97 (s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 169
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { R4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 169A
tert-butyl 3-((4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-42-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
nitrophenylamino)methyl)morpholine-4-carboxylate
The title compound was prepared as described in EXAMPLE 53B by replacing 1-
acetylpiperidin-4-amine with tert-butyl 3-(aminomethyl)morpholine-4-
carboxylate.
EXAMPLE 169B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-42-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-(morpholin-3-ylmethylamino)-3-
nitrophenylsulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 139B by replacing
EXAMPLE 139A with EXAMPLE 169A.
EXAMPLE 169C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { R4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B and tetrahydropyran-4-one,
respectively. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 8.77 (m,
1H), 8.57
(d, 1H), 8.05 (d, 1H), 7.84 (dd, 1H), 7.52 (m, 3H), 7.34 (m, 2H), 7.03 (m,
3H), 6.68 (dd, 1H),
6.40 (dd, 1H), 6.18 (d, 1H), 3.86 (m, 2H), 3.72 (m, 2H), 3.11 (m, 6H), 2.74
(m, 4H), 2.20 (m,
6H), 1.95 (m, 3H), 1.51 (m, 7H), 0.92 (s, 6H).
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EXAMPLE 170
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f [(4-cyclobutylmorpholin-3-yl)methyll amino I -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B and cyclobutanone. 1H NMR
(300 MHz, dimethylsulfoxide-d6) 8 11.68 (s, 1H), 8.72 (s, 1H), 8.57 (d, 1H),
8.04 (d, 1H),
7.84 (dd, 1H), 7.52 (m, 3H), 7.34 (m, 3H), 7.03 (m, 4H), 6.67 (dd, 1H), 6.39
(dd, 1H), 6.18
(d, 1H), 3.47 (m, 3H), 3.10 (m, 6H), 2.72 (m, 6H), 2.25 (m, 8H), 1.95 (m, 4H),
1.56 (m, 3H),
1.38 (m, 2H), 0.92 (s, 6H).
EXAMPLE 171
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { R4-tetrahydrofuran-3-ylmorpholin-3-yl)methyllamino }
phenyl)sulfony11-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 139C by replacing
EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B and 3-oxotetrahydrofuran,
respectively. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.64 (s, 1H), 8.66 (s,
1H), 8.53
(d, 1H), 8.01 (d, 1H), 7.80 (d, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H),
6.98 (d, 1H),
6.66 (dd, 1H), 6.37 (d, 1H), 6.19 (d, 1H), 3.68 (m, 8H), 3.05 (m, 6H), 2.85
(m, 3H), 2.73 (s,
2H), 2.25 (m, 6H), 1.91 (m, 3H), 1.37 (m, 3H), 0.95 (m, 6H).
EXAMPLE 172
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R{ 1- [2-fluoro-1-(fluoromethyBethyllpiperidin-4-yl} methyl)amino] -3 -
nitrophenyl I sulfony1)-
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 163B for tert-butyl
piperazine-l-carboxylate and 1,3-difluoropropan-2-one for 4'-chlorobipheny1-2-
carboxaldehyde in EXAMPLE 1A. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67
(s,
1H), 11.40 (br s, 1H), 8.57 (m, 2H), 8.03 (d, 1H), 7.78 (d, 1H), 7.50 (m, 3H),
7.34 (d, 2H),
7.07 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (m 1H), 6.19 (d, 1H), 4.63 (d,
2H), 4.53 (d,
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2H), 3.28 (m, 2H), 3.07 (m, 4H), 2.89 (m, 2H), 2.74 (m, 2H), 2.40 (m, 2H),
2.16 (m, 6H),
1.95 (s, 2H), 1.67 (m, 3H), 1.38 (t, 2H), 1.23 (m, 3H), 0.94 (s, 6H).
EXAMPLE 173
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(1-cyclopropyl-4-fluoropiperidin-4-y1)methoxyl-3-nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 173A
4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 126B for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 173B
4-((1-cyclopropy1-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
To EXAMPLE 173A (0.24 g) in methanol (3 mL) was added 3A molecular sieves
(0.1 g), followed sequentially by acetic acid (0.31 mL), (1-
ethoxycyclopropoxy)trimethylsilane (0.64 mL), and sodium cyanoborohydride
(0.148 g). The
reaction was heated under reflux overnight. After cooling, the reaction
mixture was loaded
onto a silica gel column. After drying, the column was eluted with 100:2:0.2
ethyl
acetate/methanol/NH4OH to give the title compound.
EXAMPLE173C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
R1-cyclopropyl-4-fluoropiperidin-4-y1)methoxyl -3-nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 173B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.65 (s,
1H), 8.33 (s, 1H), 8.01 (m, 2H), 7.53 (d, 1H), 7.48-7.49 (m, 2H), 7.34-7.38
(m, 3H), 7.04 (d,
2H), 6.66 (dd, 1H), 6.38 (dd, 1H), 6.21 (d, 1H), 4.32 (d, 2H), 3.70-3.77 (m,
2H), 3.07 (s, 4H),
2.92 (s, 2H), 2.80 (s, 2H), 2.58 (s, 2H), 2.25 (s, 4H), 2.13-2.16 (m 2H), 1.38
(t, 2H), 0.92 (s,
6H), 0.40-0.49 (m, 4H).
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EXAMPLE 174
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
[(4-methoxybenzyBaminol-3-nitrophenyllsulfony1)-2-(1H-pyrrolol2,3-blpyridin-5-
yloxy)benzamide
A suspension of EXAMPLE 53A (120 mg), (4-methoxyphenyl)methanamine (31 mg)
and Hunig'sBase (0.159 mL) in dimethylsulfoxide (2 mL) was heated for 2 hours
at 150 C in
a Biotage Initiator microwave reactor. The reaction mixture was diluted with
methanol (2
mL) and purified by reverse phase HPLC (C8, 30% - 100% CH3CN/water/0.1%
trifluoroacetic acid). 1H NMR (500 MHz, pyridine-d5) 8 13.07 (s, 1H), 9.32 (d,
1H), 9.17 (t,
1H), 8.43 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.64 - 7.68 (m, 2H), 7.44 (d,
2H), 7.38 (d, 2H),
7.07 (d, 2H), 6.97 - 7.02 (m, 2H), 6.90 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H),
6.49 (dd, 1H),
4.55 (d, 2H), 3.68 (s, 3H), 3.03 - 3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H),
2.10 - 2.17 (m, 4H),
1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 175
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- l(3-
nitro-4- { [3-(trifluoromethoxy)benzyllamino}phenyl)sulfonyll-2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
The title compound was prepared by substituting (3-
trifluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE
174. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.38 (t, 1H), 9.31 (d,
1H), 8.42 (d,
1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.65 (ddd, 2H), 7.41 - 7.46 (m, 3H), 7.36 -
7.40 (m, 2H),
7.07 (d, 2H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (d, 1H), 4.73
(d, 2H), 3.02 - 3.08
(m, 4H), 2.77 (s, 2H), 2.22 - 2.28 (m, 2H), 2.09 - 2.16 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H),
0.93 (s, 6H).
EXAMPLE 176
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R3 -methoxybenzyl)aminol -3-nitrophenyllsulfony1)-2-(1H-pyrrolo [2,3-blpyridin-
5 -
yloxy)benzamide
The title compound was prepared by substituting (3-methoxyphenyl)methanamine
for
(4-methoxyphenyl)methanamine in EXAMPLE 174. 1H NMR (500 MHz, pyridine-d5) 8
13.06 (s, 1H), 9.27 - 9.32 (m, 2H), 8.42 (d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H),
7.64 - 7.67 (m,
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2H), 7.44 (d, 2H), 7.32 (t, 1H), 7.14 (s, 1H), 7.04 - 7.09 (m, 3H), 6.88 -
6.94 (m, 2H), 6.74
(dd, 1H), 6.52 (d, 1H), 6.48 - 6.50 (m, 1H), 4.64 (d, 2H), 3.68 (s, 3H), 3.03 -
3.09 (m, 4H),
2.77 (s, 2H), 2.26 (t, 2H), 2.10 - 2.18 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
EXAMPLE 177
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-[(4-
{ 1L4-(difluoromethoxy)benzyllamino}-3-nitrophenyl)sulfonyll-2-(1H-pyrrolo[2,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting (4-
difluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE
174. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.32 (d, 1H), 9.28 (t,
1H), 8.42 (d,
1H), 8.28 (dd, 1H), 8.07 (d, 1H), 7.66 (t, 1H), 7.64 (d, 1H), 7.58 (s, 1H),
7.44 (s, 2H), 7.26 (s,
1H), 7.25 (d, 1H), 7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H),
6.49 (dd, 1H), 4.64
(d, 2H), 3.03 - 3.10 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.11 - 2.17 (m, 4H),
1.97 (s, 2H), 1.39
(t, 2H), 0.93 (s, 6H).
EXAMPLE 178
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
(1,4-dioxaspiro [4.51dec-8-ylamino)-3-nitrophenyllsulfony1}-2-(1H-pyrrolo [2,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting 1,4-dioxa-spiro[4.5]dec-8-
ylamine
for 1-acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz,
dimethylsulfoxide-d6)
8 11.67 (br s, 1H), 8.55 (d, 1H), 8.26 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H),
7.54-7.46 (m, 3H),
7.35 (d, 2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.19
(d, 1H), 3.89 (s,
4H), 3.78 (m, 1H), 3.07 (br s, 4H), 2.78 (br s, 2H), 2.28-2.11 (m, 6H), 2.00-
1.88 (m, 4H),
1.75-1.57 (m, 4H), 1.54-1.35 (m, 4H), 0.92 (s, 6H).
EXAMPLE 179
Trans-N-[(4-{ [4-(acetylamino)cyclohexyllamino}-3-nitrophenyl)sulfony11-4-(4-
{ [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
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EXAMPLE 179A
tert-butyl trans-4-acetamidocyclohexylcarbamate
Tert-butyl (trans)-4-aminocyclohexylcarbamate (1.500 g) and triethylamine
(2.93 mL,
2.125 g) were added to dichloromethane and stirred until the tert-butyl
(trans)-4-
aminocyclohexylcarbamate had dissolved completely. Acetyl chloride (0.577 g)
was added
slowly, and the solution was stirred at room temperature for 16 hours. The
solvent was
removed, and the residue taken up in ethyl acetate, washed with pH 4 buffer,
washed with
brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was
concentrated under
vacuum.
EXAMPLE 179B
N-(trans-4-aminocyclohexyl)acetamide
The title compound was prepared by substituting EXAMPLE 179A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 179C
Trans-N- 11(4- { 1L4-(acetylamino)cyclohexyll amino } -3 -
nitrophenyl)sulfonyll -4-(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 179B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz, dimethylsulfoxide-d6)
8
11.67 (br s, 1H), 8.55 (d, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 7.82-7.76 (m, 2H),
7.53-7.46 (m,
3H), 7.35 (d, 2H), 7.16 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H),
6.19 (d, 1H), 3.57
(m, 2H), 3.07 (br s, 4H), 2.75 (br s, 2H), 2.28-2.10 (m, 6H), 2.03-1.94 (m,
4H), 1.83 (d, 2H),
1.80 (s, 3H), 1.55-1.24 (m, 6H), 0.92 (s, 6H).
EXAMPLE 180
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f R3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yll amino I -3 -nitrophenyl)sulfonyll
-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 180A
(R)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
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To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) and 1,1-
difluoro-2-
iodoethane (618 mg) in N,N-dimethylformamide (6 mL) was added N-ethyl-N-
isopropylpropan-2-amine (1.403 ml) and the mixture was stirred at 70 C for 72
hours. The
reaction mixture was concentrated and the crude product was purified on silica
gel with
methanol / dichloromethane.
EXAMPLE 180B
(R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
To a solution of EXAMPLE 180A (525 mg) in a mixture of dichloromethane (3 mL)
and methanol (4.0 mL) was added hydrogen chloride, 4M in dioxane (5.24 mL) and
the
reaction was stirred for 1.5 hours. The reaction was concentrated and the
crude material was
taken up in dichloromethane and the solvent evaporated, then taken up in ether
and the
solvent evaporated, and then dried on high vacuum.
EXAMPLE 180C
(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 180B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 180D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yll amino I -3-nitrophenyl)sulfonyll -
2-(1H-
pyrrolo112,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 180C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.02 (m, 1H), 9.27 (d,
1H),
8.55 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H), 7.64 - 7.68 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04 - 6.29
(m, 1H), 4.06 (m,
1H), 3.07 (m, 4H), 2.83 - 2.95 (m, 4H), 2.74 - 2.82 (m, 3H), 2.47 (m, 1H),
2.09 - 2.30 (m,
8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 181
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R3S)-1-(2-fluoroethyl)pyrrolidin-3-yll amino I -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
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EXAMPLE 181A
(S)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting 1-fluoro-2-iodoethane for 1,1-
difluoro-2-iodoethane and (S)-tert-butyl pyrrolidin-3-ylcarbamate for (R)-tert-
butyl
pyrrolidin-3-ylcarbamate in EXAMPLE 180A.
EXAMPLE 181B
(S)-1-(2-fluoroethyl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 181A for EXAMPLE
180A in EXAMPLE 180B.
EXAMPLE 181C
(S)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 181B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 181D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ 11(3S)-1-(2-fluoroethyl)pyrrolidin-3-y11amino I -3 -nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 181C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.00 (m, 1H), 9.26 (d,
1H),
8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 7.63 - 7.66 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.82 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t,
1H), 4.51 (t, 1H),
4.05 (m, 1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66 - 2.79 (m, 6H), 2.39 (q, 1H),
2.20 - 2.29 (m,
3H), 2.15 (m, 5H), 1.97 (s, 2H), 1.66 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 182
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- 11(4-
{ 11(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-y11amino I -3-nitrophenyl)sulfonyll-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
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EXAMPLE 182A
(S)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting (S)-tert-butyl pyrrolidin-3-
ylcarbamate for (R)-tert-butyl pyrrolidin-3-ylcarbamate in EXAMPLE 180A.
EXAMPLE 182B
(S)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 182A for EXAMPLE
180A in EXAMPLE 180B.
EXAMPLE 182C
(S)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 182B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 182D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f 11(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yll amino I -3-
nitrophenyl)sulfonyll-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 182C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.02 (m, 1H), 9.27 (d,
1H),
8.54 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.64 - 7.68 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.82 (d, 1H), 6.75 (dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04 - 6.29
(m, 1H), 4.06 (m,
1H), 3.07 (m, 4H), 2.83 - 2.95 (m, 4H), 2.74 - 2.82 (m, 3H), 2.47 (m, 1H),
2.09 - 2.30 (m,
8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 183
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f R3R)-1-(2-fluoroethyl)pyrrolidin-3-yll amino I -3-nitrophenyl)sulfonyll -2-
(1H-
pyrrolol2,blpyridin-5-yloxy)benzamide
EXAMPLE 183A
(R)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate
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The title compound was prepared by substituting 1-fluoro-2-iodoethane for 1,1-
difluoro-2-iodoethane in EXAMPLE 180A.
EXAMPLE 183B
(R)-1-(2-fluoroethyl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 183A for EXAMPLE
180A in EXAMPLE 180B.
EXAMPLE 183C
(R)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 183B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
ECAMPLE 183D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ R3R)-1-(2-fluoroethyl)pyrrolidin-3-y11amino I -3-nitrophenyl)sulfonyll -2-
(1H-pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 183C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine- d5) 8 13.00 (m, 1H), 9.26 (d,
1H),
8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 7.63 - 7.66 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t,
1H), 4.50 (t, 1H),
4.04 (m, 1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66 - 2.79 (m, 6H), 2.39 (q, 1H),
2.19 - 2.28 (m,
3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.66 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 184
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(3 -
nitro-4- { R3S)-1-oxetan-3-ylpyrrolidin-3-yllmethoxy }phenyl)sulfonyll-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 184A
(S)-tert-butyl 3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate
To a solution of (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate
(0.300 g)
in tetrahydrofuran (5 mL) was added sodium hydride (0.238 g). After stirring
for 15 minutes,
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4-fluoro-3-nitrobenzenesulfonamide (0.295 g) was added and reaction stirred at
room
temperature. After 1 hour, the reaction was partitioned between water (25 mL)
and
dichloromethane (50 mL) and the reaction quenched with 1N aqueous HC1 (5.96
mL). The
organic layer was separated, dried over magnesium sulfate, filtered, and
concentrated. Silica
gel chromatography (Reveleris 12 g) eluting with a gradient of 0.2% to 2%
methanol/dichloromethane over 30 minutes (flow = 36 m/minute) gave the title
compound.
EXAMPLE 184B
(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)benzenesulfonamide
To (S)-tert-butyl 3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-
carboxylate
(0.433 g) was added hydrogen chloride (4.0M in dioxane, 1.0 mL). After
stirring for 1 hour,
the reaction was concentrated and partitioned between dichloromethane (50 mL)
and
saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was separated and

concentrated. The residue was triturated with methanol (100 mL), filtered and
concentrated
and treated with sodium cyanoborohyde (0.068 g) and cyclobutanone (0.078 g)
and stirred
overnight. The reaction was partitioned between dichloromethane (50 mL) and
water (25
mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was dried over
magnesium
sulfate, filtered, and concentrated to give the title compound.
EXAMPLE 184C
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(3-
nitro-4- { 11(3S)-1-oxetan-3-ylpyrrolidin-3-yllmethoxy } phenyl)sulfonyll -2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 184B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.64 (s, 1H), 11.45 ¨ 11.01 (m, 1H), 8.30 (d, 1H),
7.98 (dd, 2H),
7.60 ¨ 7.43 (m, 3H), 7.33 (t, 3H), 7.04 (d, 2H), 6.74 ¨ 6.59 (m, 1H), 6.37
(dd, 1H), 6.21 (d,
1H), 4.49 (td, 2H), 4.33 (s, 1H), 4.13 (dd, 2H), 3.79 (s, 2H), 3.44 (dd, 2H),
3.07 (s, 4H), 2.74
(d, 6H), 2.19 (d, 6H), 1.98 (d, 2H), 1.74 ¨ 1.52 (m, 1H), 1.39 (t, 2H), 0.92
(s, 6H).
EXAMPLE 185
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-hydroxybenzyBaminol -3 -nitrophenyl } sulfony1)-2-(1H-pyrrolo [2,3 -
blpyridin-5 -
yloxy)benzamide
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The title compound was prepared by substituting (4-hydroxyphenyl)methanamine
for
(4-methoxyphenyl)methanamine in EXAMPLE 174. 1H NMR (500 MHz, pyridine-d5) 8
13.06 (s, 1H), 11.67 (bs, 1H), 9.32 (d, 1H), 9.14 (s, 1H), 8.44 (d, 1H), 8.28
(dd, 1H), 8.09 (d,
1H), 7.65 - 7.68 (m, 2H), 7.44 (d, 2H), 7.37 - 7.41 (m, 2H), 7.19 (s, 2H),
7.07 (d, 2H), 6.93
(d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 4.54 (d, 2H), 3.02 - 3.09
(m, 4H), 2.77 (s,
2H), 2.22 - 2.29 (m, 2H), 2.10 - 2.17 (m, 4H), 1.97 (d, 2H), 1.39 (t, 2H),
0.94 (s, 6H).
EXAMPLE 186
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(3 -hydroxybenzyl)aminol -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting (3-hydroxyphenyl)methanamine
for
(4-methoxyphenyl)methanamine in EXAMPLE 174. 1H NMR (500 MHz, pyridine-d5) 8
13.06 (s, 1H), 11.67 (bs, 1H), 9.27 - 9.32 (m, 2H), 8.43 (d, 1H), 8.20 (dd,
1H), 8.08 (d, 1H),
7.66 (t, 2H), 7.44 (d, 2H), 7.33 (t, 1H), 7.25 (s, 1H), 7.13 (dd, 1H), 7.07
(d, 2H), 6.98 (d, 1H),
6.88 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.64 (d, 2H), 3.02 -
3.09 (m, 4H),
2.77 (s, 2H), 2.22 - 2.28 (m, 2H), 2.09 - 2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 187
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
113-(difluoromethoxy)benzyllaminol-3-nitropheny0sulfonyll-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting (3-
difluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE
174. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.34 (t, 1H), 9.30 (d,
1H), 8.42 (d,
1H), 8.26 (dd, 1H), 8.08 (d, 1H), 7.66 (ddd, 2H), 7.40 - 7.45 (m, 3H), 7.36
(t, 1H), 7.27 - 7.30
(m, 2H), 7.19 (d, 1H), 7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52 (d,
1H), 6.49 (dd, 1H),
4.69 (d, 2H), 3.02 - 3.08 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.09 - 2.16 (m,
4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 188
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N- { [4-
( { [cis -3 -morpholin-4-ylcyclopentyll methyl } amino)-3-nitrophenyll
sulfonyl I -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 188A
Cis-methyl 3-morpholinocyclopentanecarboxylate
The title compound was prepared by substituting methyl 3-
oxocyclopentanecarboxylate for 4'-chlorobipheny1-2-carboxaldehyde and
morpholine for tert-
butyl piperazine-l-carboxylate in EXAMPLE 1A.
EXAMPLE 188B
Cis-3-morpholinocyclopentyl)methanol
The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE
101C in EXAMPLE 101D.
EXAMPLE 188C
4-((Cis-3-morpholinocyclopentyl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 188B for (1,4-dioxan-2-

yl)methanol in EXAMPLE 12A.
EXAMPLE 188D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { [4-
( { [cis -3 -morpholin-4-ylcyclopentyll methyl } amino)-3-nitrophenyll
sulfonyl I -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 188C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d6) 6 11.57 (s, 1H),
8.17 (m,
1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.56 (d, 1H), 7.44 (t, 1H), 7.34 (m, 3H),
7.16 (m, 1H), 7.05
(d, 2H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.24 (d, 1H), 4.06 (m, 2H), 3.62 (m,
4H), 3.03 (m, 4H),
2.75 (s, 2H), 2.35 (m, 2H), 2.19 (m, 6H), 2.03 (m, 2H), 1.96 (s, 2H), 1.78 (m,
2H), 1.51 (m,
4H), 1.39 (t, 2H), 0.93 (s, 6H)
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EXAMPLE 189
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
{ [4-( { 4- Rmethylsulfonyl)aminolcyclohexyl}amino)-3-nitrophenyllsulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 189A
Trans-(4-Methanesulfonylamino-cyclohexyl)-carbamic acid tert-butyl ester
The title compound was prepared by substituting methanesulfonyl chloride for
acetyl
chloride in EXAMPLE 179A.
EXAMPLE 189B
Trans-N-(4-Aminocyclohexyl)-methanesulfonamide
The title compound was prepared by substituting EXAMPLE 189A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 189C
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyl}piperazin-1-y1)-N-
{ [4-( { 4- Rmethylsulfonyl)aminolcyclohexyl}amino)-3-nitrophenyllsulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 189B for 1-
acetylpiperidin-4-amine in EXAMPLE 53B. 1H NMR (300MHz, dimethylsulfoxide-d6)
8
11.68 (br s, 1H), 8.55 (d, 1H), 8.18 (d, 1H), 8.04 (d, 1H), 7.84 (d, 1H), 7.79
(dd, 1H), 7.56-
7.47 (m, 3H), 7.34 (d, 2H), 7.16 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39
(m, 1H), 6.19 (d,
1H), 3.56 (m, 1H), 3.17 (m, 1H), 3.07 (br s, 4H), 2.93 (s, 3H), 2.75 (br s,
2H), 2.28-2.10 (m,
6H), 2.05-1.90 (m, 6H), 1.55-1.32 (m, 6H), 0.92 (s, 6H).
EXAMPLE 190
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N4 { 4-
[(1-cyclopropylpiperidin-4-yl)amino] -3-
Rtrifluoromethyl)sulfonyllphenyllsulfony1)-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 190A
4-(1-cyclopropylpiperidin-4-ylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
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The title compound was prepared as described in EXAMPLE 17A by replacing
(tetrahydropyran-4-yl)methylamine with 4-amino-1-cyclopropylpiperidine.
EXAMPLE 190B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N-( { 4-
R1-cyclopropylpiperidin-4-yl)aminol -3- Rtrifluoromethyl)sulfonyllphenyl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 1G by replacing
EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 3J and EXAMPLE 190A, respectively.
1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.66 (s, 1H), 8.13 (d, 1H), 8.02 (d,
1H), 7.91
(m, 1H), 7.48 (m, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.67 (m, 2H), 6.38 (dd,
1H), 6.19 (d, 1H),
3.64 (m, 1H), 3.13 (m, 5H), 2.73 (m, 5H), 2.22 (m, 6H), 1.92 (m, 5H), 1.70 (m,
1H), 1.41 (m,
5H), 0.94 (s, 6H), 0.41 (m, 4H).
EXAMPLE 191
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N-( { 3-
nitro-4- R1-oxetan-3-ylpiperidin-4-yl)methoxylphenyl } sulfony1)-2-(1H-pyrrolo
[2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 191A
3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300
g) in
tetrahydrofuran (5 mL) was added sodium hydride (0.223 g). After stifling for
15 minutes, 4-
fluoro-3-nitrobenzenesulfonamide (0.276 g) was added and reaction stirred at
room
temperature. After 1 hour the reaction was partitioned between water (25 mL)
and
dichloromethane (50 mL) and the reaction quenched with 1N aqueous HC1 (5.57
mL). The
organic layer was separated, dried over magnesium sulfate, filtered, and
concentrated.
Treatment with HC1 (4.0M in dioxane, 2 mL) and methanol (2 mL) for 1 hour,
followed by
concentration, trituration with dichloromethane and filtration gave the title
compound.
EXAMPLE 191B
3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide
To a suspension of 3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide (0.100
g)
and cyclobutanone (0.030 g) in methanol (1 mL) was added sodium
cyanoborohydride (0.027
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g). After stirring overnight, the reaction was quenched with saturated NaHCO3
(5 mL) and
extracted into dichloromethane (2 x 10 mL). The organic layer was dried over
magnesium
sulfate, filtered, and concentrated to give the title compound.
EXAMPLE 191C
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 3-
nitro-4- R1-oxetan-3-ylpiperidin-4-yl)methoxylphenyl } sulfony1)-2-(1H-pyrrolo
[2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 191B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.64 (s, 1H), 11.46 - 10.46 (m, 1H), 8.29 (s, 1H),
8.00 (d, 2H), 7.61
- 7.41 (m, 3H), 7.35 (d, 3H), 7.04 (d, 2H), 6.66 (d, 1H), 6.37 (s, 1H), 6.21
(s, 1H), 4.67 - 4.40
(m, 4H), 4.08 (d, 2H), 3.06 (s, 4H), 2.78 (s, 4H), 2.19 (m, 6H), 1.96 (s, 4H),
1.79 (m, 4H),
1.39 (s, 4H), 0.93 (s, 6H).
EXAMPLE 192
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxyl -3-nitrophenyl }
sulfony1)-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 192A
4-((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-
nitrobenzenesulfonamide
A mixture of EXAMPLE 173A (0.4 g), dihydro-2H-pyran-4(3H)-one (0.179 g),
sodium cyanoborohydride (0.112 g), and acetic acid (0.5 mL) in tetrahydrofuran
(3 mL) was
stirred overnight. The solvents were removed under reduced pressure. The
residue was
purified with flash column chromatography on silica gel eluting with 100:5:0.5
ethyl
acetate/methanol/NH4OH to give the desired product.
EXAMPLE 192B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxyl -3-nitrophenyl }
sulfony1)-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 192A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.58 (s,
1H), 8.25 (s, 1H), 7.96 (d, 1H), 7.93 (d, 1H), 7.57 (d, 1H), 7.45 (t, 1H),
7.34-7.37 (m, 3H),
7.26 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.34 (dd, 1H), 6.23 (d, 1H), 4.34
(d, 2H), 3.93 (dd,
2H), 3.03 (s, 6H), 2.76 (s, 4H), 2.09-2.22 (m, 6H), 1.96 (s, 2H), 1.52-1.27
(m, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 193
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxyl -3 -
nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3 -blpyridin-5-yloxy)benzamide
EXAMPLE 193A
4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting dihydrofuran-3(2H)-one for
dihydro-2H-pyran-4(3H)-one in EXAMPLE 192A.
EXAMPLE 193B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxyl-3-
nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 193A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.63 (s,
1H), 8.31 (s, 1H), 7.99-8.00 (m, 2H), 7.54 (d, 1H), 7.46-7.48 (m, 2H), 7.34-
7.35 (m, 3H),
7.05 (d2H), 6.66 (dd, 1H), 6.37 (dd, 1H), 6.21 (d, 1H), 4.34 (d, 2H), 3.76-
3.83 (m, 3H), 3.62-
3.65 (m, 2H), 3.03 (s, 4H), 2.79 (s, 4H), 2.24 (s, 2H), 2.15 (s, 2H), 1.84-
1.99 (m, 8H), 1.52-
1.27 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 194
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
114-fluoro-1-(methylsulfonyl)piperidin-4-yllmethoxyl-3-nitrophenyl)sulfonyll-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
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EXAMPLE 194A
4-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-
nitrobenzenesulfonamide
A mixture of EXAMPLE 173A (0.4 g), methanesulfonyl chloride (0.113 g), and
triethylamine (0.64 mL) in dichloromethane (5 mL) was stirred overnight. The
reaction
mixture was loaded onto a silica gel column and eluted with 100:1 ethyl
acetate:methanol to
give the clean product.
EXAMPLE 194B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-
y1)-N-1(4-
114-fluoro-1-(methylsulfonyl)piperidin-4-yllmethoxy1-3-nitrophenyl)sulfonyll-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 194A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.66 (s,
1H), 8.37 (s, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.49-7.53 (m, 3H), 7.42 (d,
1H), 7.35 (d, 2H),
7.05 (d, 2H), 6.67 (dd, 1H), 6.38-6.39 (m, 1H), 6.21 (d, 1H), 4.40 (d, 2H),
3.51-3.54 (m, 2H),
3.09 (s, 4H), 2.96-3.01 (m, 4H), 2.92 (s, 3H), 2.82 (s, 2H), 2.25-2.34 (m,
4H), 2.13-2.16 (m,
6H), 2.01-2.07 (m, 2H0, 1.99 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 195
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyllpiperazin-1-
y1)-N-113 -
nitro-4-(11(3R)-1-oxetan-3-ylpyrrolidin-3-yllmethyllamino)phenyll sulfony11-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 195A
(R)-tert-butyl 3-((4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
nitrophenylamino)methyl)pyrrolidine-l-carboxylate
The title compound was prepared by substituting (R)-tert-butyl 3-
(aminomethyl)pyrrolidine-1-carboxylate for 1-acetylpiperidin-4-amine in
EXAMPLE 53B.
EXAMPLE 195B
(S)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-l-y1)-N-(3-nitro-4-(pyrrolidin-3-
ylmethylamino)phenylsulfonyl)benzamide
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The title compound was prepared by substituting EXAMPLE 195A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 195C
(R)-2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)-4-(4-42-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(3-nitro-4-41-(oxetan-3-y1)pyrrolidin-3-
y1)methylamino)phenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 195B for tert-butyl
piperazine-l-carboxylate and oxetan-3-one for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A. 1H NMR (500MHz, dimethylsulfoxide-d6) 11.67 (s, 1H), 8.81 (t, 1H),
8.55
(d, 1H), 8.02 (d, 1H), 7.79 (dd, 1H), 7.50 (m, 3H), 7.35 (m, 2H), 7.04 (m,
3H), 6.67 (dd, 1H),
6.39 (m, 1H), 6.19 (d, 1H), 4.57 (m, 2H), 4.48 (m, 2H), 3.68 (m, 2H), 3.30 (m,
2H), 3.06 (m,
4H), 2.74 (m, 3H), 2.56 (m, 3H), 2.44 (m, 1H), 2.18 (m, 5H), 1.95 (m, 3H),
1.58 (m, 1H),
1.36 (m, 2H), 0.94 (s, 6H).
EXAMPLE 196
Trans-4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
({ 4- R4-hydroxycyclohexyl)methoxyl -3-nitrophenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
EXAMPLE 196A
Trans-4-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-3-
nitrobenzenesulfonamide
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with trans-(4-(tert-
butyldimethylsilyloxy)cyclohexyl)methanol (made
according to the procedures in WO 2008/124878).
EXAMPLE 196B
Trans-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-N-(4-(41r,4r)-4-(tert-
butyldimethylsilyloxy)cyclohexyl)methoxy)-3-nitrophenylsulfony1)-4-(4-42-(4-
chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzamide
The title compound was prepared as described in EXAMPLE 1G using EXAMPLE
196A in place of EXAMPLE 1F and EXAMPLE 3J in place of EXAMPLE 1E.
EXAMPLE 196C
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Trans-4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-
( { 4- R4-hydroxycyclohexyl)methoxyl -3-nitrophenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
EXAMPLE 196B (150 mg) in dichloromethane (5 mL) and methanol (2 mL) was
treated with 10% aqueous HC1 (3 mL) for 1 hour and concentrated. The residue
was purified
by reverse phase HPLC on a C18 column using a gradient of 40-60% acetonitrile
in 0.1%
trifluoroacetic acid water to give the title compound as a trifluoroacetate
salt. The
trifluoroacetic acid salt was dissolved in dichloromethane (30 mL) and washed
with 50%
aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered,
and
concentrated to give the title compound. 1H NMR (400 MHz, dimethylsulfoxide-
d6) 8 11.69
(s, 1H), 11.27 (s, 1H), 8.34 (d, 1H), 7.95 - 8.08 (m, 2H), 7.47 - 7.55 (m,
3H), 7.32 - 7.40 (m,
3H), 7.01 - 7.07 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.54 (d,
1H), 3.96 - 4.06
(m, 2H), 3.10 (s, 4H), 2.84 (s, 2H), 2.05 - 2.39 (m, 6H), 1.96 (s, 2H), 1.46 -
1.93 (m, 5H),
1.39 (t, 2H), 0.98 - 1.29 (m, 4H), 0.92 (s, 6H)
EXAMPLE 197
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { [4-
(14- l3-(dimethylamino)propoxylbenzyl I amino)-3-nitrophenyllsulfonyl I -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 197A
3-(4-(aminomethyl)phenoxy)-N,N-dimethylpropan-1-amine
4-(3-(Dimethylamino)propoxy)benzonitrile (300 mg) in methanol (20 mL) was
treated with Raney nickel (wet, 1.5 g) under H2 (30 psi) for 4 hour. The
insoluble material
was filtered off and the filtrate was concentrated to provide the title
compound.
EXAMPLE 197B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N- { [4-
(14- l3-(dimethylamino)propoxylbenzyl I amino)-3-nitrophenyllsulfonyl I -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 120B using EXAMPLE
197A in place of EXAMPLE 120A. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.56
(s,
1H), 8.80 (t, 1H), 8.42 (d, 1H), 7.93 (d, 1H), 7.52 - 7.61 (m, 2H), 7.41 -
7.47 (m, 1H), 7.26 -
7.36 (m, 5H), 7.03 - 7.08 (m, 2H), 6.89 (d, 2H), 6.73 (d, 1H), 6.61 (dd, 1H),
6.31 (dd, 1H),
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6.22 (d, 1H), 4.52 (d, 2H), 3.99 (t, 2H), 2.90 - 3.05 (m, 7H), 2.72 (s, 2H),
2.61 (s, 6H), 2.09 -
2.24 (m, 6H), 1.89 - 2.04 (m, 5H), 1.38 (t, 2H), 0.92 (s, 6H)
EXAMPLE 198
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- [(4-
{ 1L4-(2-morpholin-4-ylethoxy)benzyllamino}-3-nitrophenyl)sulfony11-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 198A
(4-(2-morpholinoethoxy)phenyl)methanamine
The title compound was prepared as described in EXAMPLE 197A using 4-(2-
morpholinoethoxy)benzonitrile in place of 4-(3-
(dimethylamino)propoxy)benzonitrile.
EXAMPLE 198B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- [(4-
{ [4-(2-morpholin-4-ylethoxy)benzyllamino}-3-nitrophenyl)sulfony11-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 120B using EXAMPLE
198A in place of EXAMPLE 120A. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.69
(s,
1H), 9.00 (t, 1H), 8.56 (d, 1H), 8.02 (d, 1H), 7.72 (dd, 1H), 7.46 - 7.54 (m,
3H), 7.27 - 7.36
(m, 4H), 7.01 - 7.07 (m, 2H), 6.89 - 6.95 (m, 3H), 6.66 (dd, 1H), 6.38 (dd,
1H), 6.18 (d, 1H),
4.56 (d, 2H), 4.07 (t, 2H), 3.54 - 3.61 (m, 4H), 3.06 (s, 4H), 2.71 - 2.78 (m,
4H), 2.07 - 2.24
(m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 199
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- { [4-
( { [(E)-4-hydroxy-1-adamantyllmethyl}amino)-3-nitrophenyllsulfony11-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 199A
4-[((E)-4-Hydroxy-adamantan-1-ylmethyl)-aminol-3-nitro-benzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and 5-(aminomethyl)adamantan-2-ol
(0.6
g) in tetrahydrofuran (10 mL) were treated with triethylamine (1 mL)
overnight. The reaction
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mixture was concentrated and the residue was purified by reverse phase HPLC,
eluting 40-
60% acetonitrile in 0.1 trifluoroacetic acid water to give two isomers, which
were temporarily
assigned as EXAMPLE 199A and EXAMPLE 199B, respectively.
EXAMPLE 199B
4-[((Z)-4-Hydroxy-adamantan-1-ylmethy1)-amino[-3-nitro-benzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and 5-(aminomethyl)adamantan-2-ol
(0.6
g) in tetrahydrofuran (10 mL) were treated with triethylamine (1 mL)
overnight. The reaction
mixture was concentrated and the residue was purified by reverse phase HPLC,
eluting 40-
60% acetonitrile in 0.1 trifluoroacetic acid water to give two isomers, which
were temporarily
assigned as EXAMPLE 199A and EXAMPLE 199B, respectively.
EXAMPLE 199C
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
({ RE)-4-hydroxy-1-adamantyl[methyl}amino)-3-nitrophenyfl sulfony11-2-(1H-
pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
199A in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.68
(s,
1H), 11.40 (s, 1H), 8.55 (d, 1H), 8.50 (t, 1H), 8.03 (d, 1H), 7.77 (dd, 1H),
7.46 - 7.54 (m,
3H), 7.31 - 7.38 (m, 2H), 7.14 (d, 1H), 7.01 - 7.06 (m, 2H), 6.68 (dd, 1H),
6.38 (dd, 1H), 6.19
(d, 1H), 4.61 (d, 1H), 3.63 (d, 1H), 3.02 - 3.16 (m, 6H), 2.75 (s, 2H), 2.17
(d, 6H), 2.04 (d,
2H), 1.95 (s, 2H), 1.76 - 1.88 (m, 3H), 1.49 - 1.61 (m, 6H), 1.38 (t, 2H),
1.29 (d, 2H), 0.92 (s,
6H).
EXAMPLE 200
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { [(Z)-4-hydroxy-1-adamantyllmethyl}amino)-3-nitrophenyl[sulfony11-2-(1H-
pyrrolo[2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
199B in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.68
(s,
1H), 11.39 (s, 1H), 8.55 (d, 1H), 8.51 (t, 1H), 8.04 (d, 1H), 7.77 (dd, 1H),
7.46 - 7.55 (m,
3H), 7.31 - 7.37 (m, 2H), 7.14 (d, 1H), 7.01 - 7.06 (m, 2H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.19
(d, 1H), 4.61 (d, 1H), 3.61 (d, 1H), 3.08 (d, 6H), 2.75 (s, 2H), 2.17 (d, 6H),
1.79 - 1.99 (m,
7H), 1.55 - 1.69 (m, 4H), 1.49 (s, 2H), 1.38 (t, 2H), 1.22 (d, 2H), 0.92 (s,
6H).
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EXAMPLE 201
N-(14- IL(1S,4S)-bicyclo12.2.11hept-5-en-2-ylmethoxyl -3-nitrophenyllsulfony1)-
4-(4-1 [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 201A
4-((1S,4S)-bicyclo12.2.11hept-5-en-2-ylmethoxy)-3-nitrobenzenesulfonamide
The title compound was prepared as described in EXAMPLE 12A by replacing (1,4-
dioxan-2-yl)methanol with (1S,4S)-bicyclo12.2.11hept-5-en-2-ylmethanol.
EXAMPLE 201B
N-(14- IL(1S,4S)-bicyclo12.2.11hept-5-en-2-ylmethoxyl -3-nitrophenyllsulfony1)-
4-(4-1 [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
201A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d6) 8 11.69
(s,
1H), 8.35 (d, 1H), 7.95 - 8.10 (m, 2H), 7.47 - 7.58 (m, 3H), 7.30 - 7.45 (m,
3H), 7.04 (d, 2H),
6.68 (dd, 1H), 6.40 (d, 1H), 5.92 - 6.23 (m, 3H), 3.65 - 4.39 (m, 3H), 3.00 -
3.22 (m, 4H),
2.76 - 2.98 (m, 4H), 2.28 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.71 - 1.91 (m,
1H), 1.33 - 1.47
(m, 3H), 1.20 - 1.32 (m, 2H), 0.92 (s, 6H), 0.50 - 0.66 (m, 1H).
EXAMPLE 202
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(1-methy1-5-oxopyrrolidin-3 -yl)aminol -3 -nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 82 (140 mg) was dissolved in dioxane (3.0 mL), and 4-amino-1-
methylpyrrolidin-2-one hydrochloride (30 mg) and triethylamine (0.100 mL) were
added.
The reaction mixture was heated at 110 C for 40 hours. The reaction was
concentrated and
the crude material was purified by preparative HPLC using a C18 column, 250 x
50 mm,
1011, and eluting with a gradient of 20-100% CH3CN vs. 0.1% trifluoroacetic
acid in water,
giving the product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6
mL) and washed with 50% aqueous NaHCO3. The organic layer was dried over
anhydrous
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Na2SO4 and concentrated to give the title compound. 1H NMR (400 MHz,
dimethylsulfoxide-
d6) 8 11.65 (s, 1H), 8.74 (d, 1H), 8.37 (br d, 1H), 8.02 (d, 1H), 7.83 (dd,
1H), 7.49 (m, 3H),
7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.21
(d, 1H), 4.46 (m,
1H), 3.81 (dd, 1H), 3.38 (dd, 1H), 3.08 (br m, 4H), 2.82 (dd, 1H), 2.75 (s,
5H), 2.43 (dd, 1H),
2.21 (br m, 4H), 2.16 (br t, 2H), 1.95 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 203
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(4-
{ R1R,4R,5R,6S)-5,6-dihydroxybicyclo [2.2.11hept-2-yl[methoxy}-3 -
nitrophenyl)sulfony11-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 203A
4-(((1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.11heptan-2-yl)methoxy)-3-
nitrobenzenesulfonamide
To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) and water (1
mL) was added N-methylmorpholine N-oxide (184 mg) and 0s04 (2.5% in 2-methy1-2-

propanol) (1.05 mL). The reaction mixture was stirred overnight and purified
by reverse
phase HPLC to provide two isomers, which were temporarily assigned as EXAMPLE
203A
and EAMPLE 203B, respectively.
EXAMPLE 203B
4-(((1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.11heptan-2-yl)methoxy)-3-
nitrobenzenesulfonamide
To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) and water (1
mL) was added N-methylmorpholine N-oxide (184 mg) and 0s04 (2.5% in 2-methy1-2-

propanol) (1.05 mL). The reaction mixture was stirred overnight and purified
by reverse
phase HPLC to provide two isomers, which were temporarily assigned as EXAMPLE
203A
and EAMPLE 203B, respectively.
EXAMPLE 203C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(4-
{ R1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.11hept-2-yl[methoxy}-3-
nitrophenyl)sulfony11-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
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The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
203A in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.68
(s,
1H), 8.33 (s, 1H), 7.97 - 8.07 (m, 2H), 7.48 - 7.55 (m, 3H), 7.41 (d, 1H),
7.32 - 7.37 (m, 2H),
7.02 - 7.07 (m, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.58 (dd,
2H), 4.07 - 4.19 (m,
2H), 3.82 (t, 1H), 3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09 - 2.34 (m,
8H), 2.04 - 2.09 (m,
2H), 1.93 - 2.01 (m, 3H), 1.62 - 1.77 (m, 2H), 1.39 (t, 2H), 1.11 (d, 1H),
0.92 (s, 6H), 0.67 -
0.76 (m, 1H).
EXAMPLE 204
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(4-
{ R1R,4R,5S,6R)-5,6-dihydroxybicyclo [2.2.11hept-2-yl[methoxy}-3 -
nitrophenyl)sulfonyll -2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
203B in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.68
(s,
1H), 8.33 (s, 1H), 7.98 - 8.07 (m, 2H), 7.49 - 7.54 (m, 3H), 7.41 (d, 1H),
7.32 - 7.36 (m, 2H),
7.02 - 7.07 (m, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.58 (dd,
2H), 4.13 (dd, 2H),
3.82 (t, 1H), 3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09 - 2.35 (m, 8H),
2.07 (s, 2H), 1.93 -
2.02 (m, 3H), 1.61 - 1.80 (m, 2H), 1.39 (t, 2H), 1.11 (d, 1H), 0.92 (s, 6H),
0.66 - 0.78 (m,
1H).
EXAMPLE 205
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-({ 3-
nitro-4- [(3 -oxocyclohexyl)methoxy[phenyl}sulfony1)-2-(1H-pyrrolo [2,3 -
b[pyridin-5 -
yloxy)benzamide
EXAMPLE 205A
Methyl 1,4-dioxaspiro[4.51decane-7-carboxylate
To a solution of trimethylsilyltrifluoromethanesulfonate (0.034 mL) in dry
dichloromethane (5 mL) was added 1,2-bis(trimethylsiloxy)ethane (4.55 mL)
followed by
methyl 3-oxocyclohexanecarboxylate (2.9 g). The reaction mixture was stirred
for 3 hours at
-78 C. The reaction mixture was quenched with dry pyridine (0.5 mL), poured
into saturated
aqueous NaHCO3, and extracted with ether. The ether layer was dried over
Na2CO3 /
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Na2SO4. The reaction mixture was concentrated and purified by flash
chromatography on
silica with 5 to 30% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 205B
1,4-dioxaspiro14.51decan-7-ylmethanol
The title compound was prepared by substituting EXAMPLE 205A for EXAMPLE
101C in EXAMPLE 101D.
EXAMPLE 205C
3-nitro-4-((3-oxocyclohexyl)methoxy)benzenesulfonamide
Into a 250 mL round-bottomed flask was added sodium hydride (0.5 g) in
tetrahydrofuran (10 mL) and then 1,4-dioxaspiro14.51decan-7-ylmethanol (0.5 g)
was added.
After the mixture stirred at room temperature for 20 minutes, 4-fluoro-3-
nitrobenzenesulfonamide (0.65 g) was added. The mixture was stirred at room
temperature
for overnight. Water (20 mL) was added slowly. The aqueous layer was extracted
by
dichloromethane (3x 20 mL). The combined organic layers were dried over
Na2SO4. After
filtration, and concentration of the filtrate, the residue was purified by
reverse phase
chromatography, eluting with 30-60% acetonitrile in water with 0.1%
trifluoroacetic acid.
EXAMPLE 205D
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(13-
nitro-4-1(3 -oxocyclohexyl)methoxylphenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 205C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, dimethylsulfoxide-d6) 6 11.59 (s, 1H),
8.22 (s,
1H), 7.96 (d, 1H), 7.87 (m, 1H), 7.55 (d, 1H), 7.45 (t, 1H), 7.35 (m, 3H),
7.20 (m, 1H), 7.04
(d, 2H), 6.64 (dd, 1H), 6.34 (m, 1H), 6.23 (d, 1H), 4.07 (d, 2H), 3.04 (m,
4H), 2.76 (s, 2H),
2.35 (m, 2H), 2.20 (m, 8H), 1.96 (m, 4H), 1.58 (m, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
EXAMPLE 206
4-(4-112-(4-chloropheny1)-5,5-dimethylcyclohexa-1,3-dien-1-yllmethyllpiperazin-
1-y1)-N-
(13-nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 206A
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2-chloro-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde
In a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in
dichloromethane (30 mL), and the mixture was cooled to -10 C. Phosphoryl
trichloride (4
mL) was added dropwise, and the solution was warmed up to room temperature.
4,4-
Dimethylcyclohex-2-enone (5.5 mL) was then added slowly, and the mixture was
heated to
reflux overnight. The reaction mixture was cooled and quenched with a 0 C
solution of
sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with
diethyl ether
(200 mL x3). The combined organic layers were dried over Na2SO4, filtered, and

concentrated to give the product.
EXAMPLE 206B
2-(4-chloropheny1)-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde
Into a 1 L round-bottomed flask was added EXAMPLE 206A (6.8 g), 4-
chlorophenylboronic acid (6.5 g), and palladium (II) acetate (0.2 g) in water
(100 mL) to give
a suspension. Potassium carbonate (15 g) and tetrabutylammonium bromide (10 g)
were
added. After degassing, the mixture was stirred at 45 C for 4 hours. After
cooling and
filtering though silica gel in a funnel, diethyl ether (4x 200mL) was used to
extract the
product. The combined organic layers were dried over Na2SO4, and filtered. The
filtrate was
concentrated and purified by flash chromatography on silica with 0-10% ethyl
acetate in
hexanes to provide the title compound.
EXAMPLE 206C
Methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-5,5-
dimethylcyclohexa-1,3-dienyl)methyl)piperazin-1-y1)benzoate
The title compound was prepared by substituting EXAMPLE 206B for 4'-
chlorobipheny1-2-carboxaldehyde and EXAMPLE 15F for tert-butyl piperazine-l-
carboxylate in EXAMPLE 1A.
EXAMPLE 206D
2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-5,5-
dimethylcyclohexa-1,3-
dienyl)methyl)piperazin-1-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 206C for EXAMPLE
101E in EXAMPLE 101F.
EXAMPLE 206E
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4-(4- { 1L2-(4-chloropheny1)-5,5-dimethylcyclohexa-1,3-dien-1-
yl[methyl}piperazin-1-y1)-N-
({ 3-nitro-4- [fletrahydro-2H-pyran-4-ylmethyBamino[phenyl}sulfonyl)-2-(1H-
pyrrolo [2,3 -
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 206D for EXAMPLE 3J
and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. 1H NMR (400 MHz,
dimethylsulfoxide-d6) 6 11.61 (s, 1H), 8.49 (m, 2H), 7.99 (m, 1H), 7.72 (m,
1H), 7.53 (d,
1H), 7.41 (m, 4H), 7.12 (d, 2H), 6.99 (m, 1H), 6.66 (dd, 1H), 6.35 (m, 1H),
6.23 (d, 1H), 5.74
(d, 1H), 5.58 (d, 1H), 3.84 (m, 2H), 3.26 (m, 4H), 3.06 (m, 4H), 2.88 (s, 2H),
2.24 (m, 6H),
1.61 (m, 2H), 1.26 (m, 3H), 1.00 (s, 6H).
EXAMPLE 207
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { (3R)-1- [2-fluoro-1-(fluoromethyBethyl[pyrrolidin-3-yllamino)-3-
nitrophenyl[sulfony11-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 207A
(R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylcarbamate for tert-butyl azetidin-3-ylcarbamate in EXAMPLE 151A.
EXAMPLE 207B
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 207A for EXAMPLE
151A in EXAMPLE 151B.
EXAMPLE 207C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { (3R)-1- [2-fluoro-1-(fluoromethyBethyl[pyrrolidin-3-yllamino)-3-
nitrophenyl[sulfony11-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 207B for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.67 (s, 1H), 11.52 - 11.24 (m, 1H), 8.55 (d, 1H),
8.37 (d, 1H), 8.03
(d, 1H), 7.83 (dd, 1H), 7.57 - 7.45 (m, 3H), 7.34 (d, 2H), 7.06 (t, 3H), 6.67
(d, 1H), 6.38 (dd,
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1H), 6.20 (d, 1H), 4.70 (d, 2H), 4.54 (d, 2H), 4.23 (s, 1H), 3.11 - 2.87 (m,
7H), 2.74 (dd, 4H),
2.35 - 2.13 (m, 7H), 1.95 (s, 2H), 1.70 (s, 1H), 1.39 (d, 2H), 0.92 (s, 6H).
EXAMPLE 208
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- { [6-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl -5-(trifluoromethyl)pyridin-3-yll
sulfony11-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 208A
2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-iodo-3-
(trifluoromethyl)pyridine
A mixture of EXAMPLE 37C (0.537 g), 5-iodo-3-(trifluoromethyl)pyridin-2-ol
(1.156 g), and triphenylphosphine (1.574 g) in tetrahydrofuran (20 mL) was
cooled to 0 C.
To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.921
g). The reaction
mixture was stirred overnight. The solvent was removed, and the residue was
purified with
column flash chromatography on silica gel eluting with 4:1 hexanes/ethyl
acetate to give the
desired product.
EXAMPLE 208B
6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-
sulfonamide
EXAMPLE 207A (1.3 g) in tetrahydrofuran (10 mL) was cooled to -42 C with a
cold
bath of CH3CN/dry ice. To this solution was added 2.0 M isopropylmagnesium
chloride (1.6
mL) dropwise over 5 minutes. The reaction mixture was stirred for 30 minutes
at -42 C, then
allowed to warm to 0 C over 10 minutes. The reaction mixture was cooled again
to -42 C,
and SO2 was bubbled though it for 10 minutes. The reaction mixture was stirred
for another
30 minutes. To this solution was sulfuryl dichloride (0.433 g). On warming to
room
temperature, concentrated NH4OH (10 mL) was added and the reaction mixture was
stirred
for another 2 hours. The reaction mixture was partitioned between water and
ethyl acetate.
The aqueous layer was extracted with additional ethyl acetate three times. The
combined
organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The
residue was purified by flash column chromatography on silica gel eluting with
3:1 hexanes/
ethyl acetate to give the title compound.
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EXAMPLE 208C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-116-
1(4-fluorotetrahydro-2H-pyran-4-y1)methoxyl -5-(trifluoromethyl)pyridin-3-yll
sulfonyll-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 208B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.61 (s,
1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.42-7.47 (m,
2H), 7.36 (d, 2H),
7.05 (d, 2H), 6.66 (dd, 1H), 6.35 (s, 1H), 6.23 (s, 1H), 4.56 (d, 2H), 3.75-
3.79 (m, 2H), 3.56-
3.61 (m, 2H), 3.09 (s, 4H), 2.32-2.37 (m, 2H), 2.16(s, 2H), 1.97-1.99 (m, 2H),
1.79-1.86 (m,
4H), 1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 209
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-113-
nitro-4-(1R3S)-1-oxetan-3-ylpyrrolidin-3-yllmethyllamino)phenyllsulfony11-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 209A
(S)-tert-butyl (1-(oxetan-3-yl)pyrrolidin-3-yl)methylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
ylmethylcarbamate for tert-butyl piperazine-l-carboxylate and 3-oxetanone for
4'-
chlorobipheny1-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 209B
(S)-(1-(oxetan-3-yl)pyrrolidin-3-yl)methanamine
The title compound was prepared by substituting EXAMPLE 209A for (S)-1-tert-
butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate in EXAMPLE 168A.
EXAMPLE 209C
(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
nitrobenzenesulfonamide
for 4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 209B for 4-methylpiperazin-
1-
amine dihydrochloride in EXAMPLE 6A.
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EXAMPLE 209D
4-(4-11L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1 [3-
nitro-4-(1R3S)-1-oxetan-3 -ylpyrrolidin-3 -yll methyllamino)phenyll sulfony11-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 209C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.05 (s, 1H), 9.30 (d,
1H), 9.02
(t, 1H), 8.42 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 7.67 (dd, 2H), 7.44 (d,
2H), 7.07 (d, 2H),
6.82 (d, 1H), 6.75 (m, 1H), 6.52 (m, 2H), 4.82 (t, 1H), 4.75 (t, 1H), 4.67 (t,
2H), 3.57 (m,
1H), 3.24 (t, 2H), 3.07 (m, 4H), 2.75 (m, 3H), 2.57 (dd, 1H), 2.45 (s, 1H),
2.36 (t, 1H), 2.26
(s, 2H), 2.18 (m, 5H), 1.93 (m, 3H), 1.56 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 210
Trans-N-(15-chloro-6- R4-methoxycyclohexyl)methoxyl pyridin-3-yllsulfony1)-4-
(4-1 [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 210A
(4-methoxycyclohexyl)methanol
The title compound was prepared by substituting 4-methoxycyclohexanecarboxylic
acid for 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate in EXAMPLE
126A.
EXAMPLE 210B
Trans-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 210A for tetrahydro-
2H-pyran-4-yl)methanol and EXAMPLE 40A for 4-fluoro-3-nitrobenzenesulfonamide
in
EXAMPLE 24A.
EXAMPLE 210C
Trans-N-(15-chloro-6- R4-methoxycyclohexyl)methoxylpyridin-3-yllsulfony1)-4-(4-
1 [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 210C for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s,
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1H), 8.50 (s, 1H), 8.17 (s, 1H), 8.02 (d, 1H), 7.49-7.54 (m, 3H), 7.35 (d,
2H), 7.05 (d, 2H),
6.67 (dd, J 1H), 6.39 (s, 1H), 6.21 (s, 1H), 4.20 (d, 2H), 3.23 (s, 3H), 3.06-
3.09 (m, 4H), 2.15-
2.37 (m, 4H), 1.96-2.03 (m, 4H), 1.74-1.84 (m, 2H), 1.40 (t, 2H), 1.04-1.13
(m, 4H), 0.93 (s,
6H).
EXAMPLE 211
Cis-N-(15-chloro-6-R4-methoxycyclohexyl)methoxylpyridin-3-yll sulfony1)-4-(4-
1[2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl I piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 211A
Cis-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide
The title compound was isolated as a by-product in the synthesis of EXAMPLE
210B.
EXAMPLE 211B
Cis-N-(15-chloro-6-R4-methoxycyclohexyl)methoxylpyridin-3-yl I sulfony1)-4-(4-
1[2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl I piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 211A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.67 (s,
1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H), 7.49-7.54 (m, 3H), 7.35 (d,
2H), 7.05 (d, 2H),
6.68 (dd, 1H), 6.39 (s, 1H), 6.21 (s, 1H), 4.21 (d, 2H), 3.20 (s, 3H), 3.06
(s, 4H), 2.15-2.37
(m, 4H), 1.96 (s, 2H), 1.80-1.84 (m, 2H), 1.50-1.54 (m, 2H), 1.34-1.44 (m,
6H), 0.93 (s, 6H).
EXAMPLE 212
4-(4-1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl I piperazin-l-
y1)-N- R3 -
nitro-4-1R3S)-1-oxetan-3-ylpyrrolidin-3 -yll amino I phenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 212A
(S)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate
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The title compound was prepared by substituting (S)-tert-butyl pyrrolidin-3-
ylcarbamate for tert-butyl piperazine-l-carboxylate and 3-oxetanone for 4'-
chlorobipheny1-2-
carboxaldehyde in EXAMPLE 1A.
EXAMPLE 212B
(S)-1-(oxetan-3-yl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 212A for (S)-1-tert-
butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate in EXAMPLE 168A.
EXAMPLE 212C
(S)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
nitrobenzenesulfonamide
for 4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 212B for 4-methylpiperazin-
1-
amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 212D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { R3S)-1-oxetan-3-ylpyrrolidin-3-yll amino } phenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 212C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.03 (s, 1H), 9.27 (d,
1H), 8.58
(d, 1H), 8.42 (d, 1H), 8.37 (dd, 1H), 8.09 (d, 1H), 7.67 (t, 1H), 7.64 (d,
1H), 7.44 (d, 2H),
7.07 (d, 2H), 6.86 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67
(m, 4H), 4.09 (m,
1H), 3.59 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.69 (m, 2H), 2.62 (dd, 1H),
2.28 (m, 4H),
2.14 (m, 4H), 1.97 (s, 2H), 1.68 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 213
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R { 4- [2-(2-methoxyethoxy)ethyllmorpholin-2-yl} methyl)aminol -3 -nitrophenyl
I sulfony1)-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 213A
4-((4-(2-(2-methoxyethoxy)ethyl)morpholin-2-yl)methylamino)-3-
nitrobenzenesulfonamide
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The title compound was prepared by substituting 2-(2'-methoxyethoxy)ethyl
bromide
for methyl iodide in EXAMPLE 134B.
EXAMPLE 213B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
R{ 4- [2-(2-methoxyethoxy)ethyllmorpholin-2-yl} methyBamino1-3-nitrophenyl I
sulfony1)-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 213A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 12.98 (s, 1H), 9.26 (d,
1H),
8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.91 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.96-3.86 (m,
2H),3.72 (dd, 1H),
3.67-3.61 (m, 4H), 3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.28 (s, 3H), 3.07 (m,
4H), 2.95 (d, 1H),
2.77 (s, 2H), 2.70 (m, 1H), 2.60 (t, 2H), 2.30-2.05 (m, 8H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94 (s,
6H).
EXAMPLE 214
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ [4-(cyanomethyl)morpholin-2-yll methyl } amino)-3-nitrophenyl] sulfonyl I -
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 214A
4-((4-(cyanomethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting 2-bromoacetonitrile for methyl

iodide in EXAMPLE 134B.
EXAMPLE 214B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
({ [4-(cyanomethyl)morpholin-2-yll methyl } amino)-3-nitrophenyl] sulfonyl I -
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 214A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.01 (s, 1H), 9.26 (d,
1H),
8.86 (t, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m,
1H),3.87 (d, 1H), 3.77
(s, 2H), 3.65 (dt, 1H), 3.51-3.40 (m, 2H), 3.07 (m, 4H), 2.87 (d, 1H), 2.77
(s, 2H), 2.60 (d,
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1H), 2.50 (m, 1H), 2.38 (t, 1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94
(s, 6H).
EXAMPLE 215
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
( { 1L4-(N,N-dimethylglycyl)morpholin-2-yl[methyl}amino)-3-
nitrophenyllsulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 215A
4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting 2-dimethylaminoacetyl chloride

hydrochloride for methyl iodide in EXAMPLE 134B.
EXAMPLE 215B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [4-
( { [4-(N,N-dimethylglycyl)morpholin-2-yl[methyl}amino)-3-
nitrophenyllsulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 215A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.27 (d,
1H),
8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (dd, 1H), 6.75 (d, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H),
4.20 (dd, 1H),
3.95-3.76 (m, 2H),3.60-3.40 (m, 3H),3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m,
4H), 2.80
(m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94
(s, 6H).
EXAMPLE 216
(2- { [(4- { [4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-y1)-
2-(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzoyllsulfamoy11-2-
nitrophenyBaminolmethyllmorpholin-4-y1)acetic acid
EXAMPLE 216A
tert-butyl 2-(2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholino)acetate
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The title compound was prepared by substituting tert-butyl 2-bromoacetate for
methyl
iodide in EXAMPLE 134B.
EXAMPLE 216B
tert-butyl 2-(2-((4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoyl)sulfamoy1)-2-
nitrophenylamino)methylnuorpholino)acetate
The title compound was prepared by substituting EXAMPLE 216A for EXAMPLE
130C in EXAMPLE 130D.
EXAMPLE 216C
(2-11(4-114-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-y1)-
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzoyllsulfamoy11-2-
nitrophenyBaminolmethyllmorpholin-4-yl)acetic acid
The title compound was prepared by treating EXAMPLE 216B with 50%
trifluoroacetic acid in dichloromethane. 1H NMR (500MHz, pyridine-d5) 8 12.97
(s, 1H),
9.26 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.30 (dd, 1H), 8.12 (d, 1H), 7.69
(t, 1H), 7.64 (d, 1H),
7.43 (d, 2H), 7.08 (d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.55 (d, 1H), 6.47
(m, 1H), 4.05-4.00
(m, 1H),3.91 (d, 1H), 3.79 (dt, 1H), 3.50 (s, 2H), 3.45 (m, 2H), 3.13 (d, 1H),
3.07 (m, 4H),
2.88 (d, 1H), 2.78 (s, 2H), 2.57 (dt, 1H), 2.43 (t, 1H), 2.26 (m, 2H), 2.14
(m, 4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 217
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-113 -
nitro-4-(114-(oxetan-3-yl)morpholin-2-yllmethyllamino)phenyll sulfony11-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 217A
The title compound was prepared by substituting EXAMPLE 134A for tert-butyl
piperazine-l-carboxylate and 3-oxetanone for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A.
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EXAMPLE 217B
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-{ [3-
nitro-44 { 1L4-(oxetan-3-yl)morpholin-2-yll methyl } amino)phenyl] sulfonyl I -
2-(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 217A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.26 (d,
1H),
8.87 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.64 (m, 4H),
3.93 (m, 1H),3.89
(d, 1H), 3.68 (dt, 1H), 3.53-3.35 (m, 3H), 3.07 (m, 4H), 2.77 (s, 2H), 2.72
(d, 1H), 2.44 (d,
1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.85 (t, 1H), 1.39 (t, 2H),
0.94 (s, 6H).
EXAMPLE 218
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f [(4-cyclopropylmorpholin-2-yl)methyllamino I -3-nitrophenyl)sulfony11-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 218A
4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 134A for EXAMPLE
173A in EXAMPLE 173B.
EXAMPLE 218B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- [O-
f [(4-cyclopropylmorpholin-2-yl)methyllamino I -3-nitrophenyl)sulfony11-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 218A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.26 (d,
1H),
8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H),
3.84-3.81 (m,
1H),3.59 (dt, 1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s,
2H), 2.69 (d, 1H),
2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14 (m, 4H), 1.97 (s, 2H), 1.58
(m, 1H), 1.39 (t,
2H), 0.94 (s, 6H), 0.45-0.39 (m, 4H).
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EXAMPLE 219
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N- { 115-
(methylsulfony1)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfonyl I -
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 219A
5-(methylthio)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
A mixture of EXAMPLE 36B (0.1 g) and sodium methanethiolate (0.04 g) in N,N-
dimethylformamide (2 mL) was heated at 80 C overnight. After cooling, the
reaction mixture
was partitioned between water and ethyl acetate. The organic layer was
separated, and the
aqueous layer was extracted with additional ethyl acetate three times. The
combined organic
layers were washed with brine, dried over MgSO4, filtered, and concentrated.
The residue
was purified by flash column chromatography on silica gel using 10-50% ethyl
acetate in
hexanes to provide the title compound.
EXAMPLE 219B
5-(methylsulfony1)-6-(fletrahydro-2H-pyran-4-y0methoxy)pyridine-3-sulfonamide
A mixture of EXAMPLE 219A (0.15 g) and 75% meta-chloroperoxybenzoic acid
(0.217 g) in chloroform (4 mL) was stirred at room temperature. The reaction
mixture was
stirred overnight. The reaction mixture was then partitioned between ethyl
acetate and water.
The organic layer was separated, and the aqueous layer was extracted with
additional ethyl
acetate three times. The combined organic layers were washed with brine, dried
over MgSO4,
filtered, and concentrated. The residue was purified by flash column
chromatography on
silica gel using 10-50% ethyl acetate in hexanes to provide the title
compound.
EXAMPLE 219C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N- { 115-
(methylsulfony1)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yll sulfonyl I -
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 219B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.65 (s,
1H), 8.81 (s, 1H), 8.55 (d, 1H), 8.01 (d, 1H), 7.55 (d, 1H), 7.49-7.50 (m,
2H), 7.37 (d, 2H),
7.05 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.21 (d, 1H), 4.36 (d, 2H), 3.88
(dd, 2H), 3.13 (s,
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4H), 2.95 (s, 2H), 2.36-2.38 (m, 2H), 2.03-2.16 (m, 4H), 1.97 (s, 3H), 1.66-
1.69 (m, 2H),
1.38-1.402 (m, 4H), 0.93 (s, 6H).
EXAMPLE 220
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl -3-
Rtrifluoromethyl)sulfonyllphenyl I sulfony1)-
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 220A
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
To a solution of EXAMPLE 37C (0.500 g) in tetrahydrofuran (5 mL) was added
sodium hydride (0.596 g). Additional tetrahydrofuran (25 mL) was added and the
mixture
stirred for 30 minutes, then 4-fluoro-3-
(trifluoromethylsulfonyl)benzenesulfonamide (1.145
g) was added as a solution in tetrahydrofuran (5 mL). After stirring for 2
hours, the reaction
mixture was pardoned between 1N aqueous HC1 (50 mL) and dichloromethane (200
mL).
The organic layer was dried over magnesium sulfate, filtered, and
concentrated. The
resulting solid was chromatographed over silica gel (Reveleris 80g) eluting
with a gradient of
0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow = 40 mL/min) to
provide the
title compound.
EXAMPLE 220B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl -3-
Rtrifluoromethyl)sulfonyllphenyl I sulfony1)-
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 220A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.66 (s, 1H), 8.42 (s, 1H), 8.35 - 8.22 (m, 1H), 8.01
(s, 1H), 7.49 (d,
4H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (s, 1H), 6.38 (s, 1H), 6.21 (s, 1H),
4.42 (d, 2H), 3.76 (s,
2H), 3.59 (s, 2H), 3.10 (s, 6H), 2.15 (s, 6H), 2.02 - 1.74 (m, 6H), 1.40 (s,
2H), 0.93 (s, 6H).
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EXAMPLE 221
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-({4-
R4-methyltetrahydro-2H-pyran-4-yl)methoxyl -3 -nitrophenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 221A
4-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting (4-methyltetrahydro-2H-pyran-4-

yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 221B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-1-
y1)-N-({4-
R4-methyltetrahydro-2H-pyran-4-yl)methoxyl -3 -nitrophenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 221A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.69 (s,
1H), 8.36 (s, 1H), 8.04-8.06 (m, 2H), 7.50-7.53 (m, 3H), 7.41 (d, 1H), 7.35
(d, 2H), 7.04 (d,
2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.00 (s, 2H), 3.63-3.67 (m,
2H), 3.53-3.58
(m, 2H), 3.09 (s, 4H), 2.82 (s, 2H), 2.27 (s, 2H), 2.15 (s, 2H), 1.58-1.63 (m,
2H), 1.39 (t, 2H),
1.30-1.34 (m, 2H), 1.09 (s, 3H), 0.92 (s, 6H).
EXAMPLE 222
ethyl 4-(4-{ [4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzoyllsulfamoyl I -2-
nitrophenyl)piperazine-1-
carboxylate
EXAMPLE 222A
ethyl 4-(2-nitro-4-sulfamoylphenyl)piperazine-1-carboxylate
The title compound was prepared by substituting ethyl piperazine-l-carboxylate
for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
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EXAMPLE 222B
ethyl 4-(4-114-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-
y1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzoyllsulfamoy11-2-
nitrophenyl)piperazine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 8 11.52 (br. s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.59
(m, 2H), 7.43 (t,
1H), 7.35 (d, 2H), 7.23 (d, 1H), 7.05 (d, 2H), 6.94 (d, 1H), 6.63 (dd, 1H),
6.29 (m, 2H), 4.07
(q, 2H), 3.47 (m, 4H), 3.17 (d, 2H), 3.00 (m, 8H), 2.73 (s, 2H), 2.18 (m, 6H),
1.96 (s, 2H),
1.39 (t, 2H), 1.20 (t, 3H), 0.93 (s, 6H).
EXAMPLE 223
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-14-
(morpholin-4-yl)piperidin-1-y11-3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 223A
The title compound was prepared by substituting 4-(piperidin-4-yl)morpholine
for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 223B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-14-
(morpholin-4-y1)piperidin-1-y11-3-nitrophenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 223A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (500 MHz,
dimethylsulfoxide-d6) 8 11.53 (br. s, 1H), 8.05 (d, 1H), 7.91 (d, 1H), 7.58
(m, 2H), 7.43 (t,
1H), 7.35 (d, 2H), 7.26 (d, 1H), 7.05 (d, 2H), 6.91 (d, 1H), 6.62 (dd, 1H),
6.29 (m, 2H), 5.76
(s, 1H), 3.57 (m, 4H), 3.20 (m, 2H), 3.01 (m, 4H), 2.80 (t, 2H), 2.73 (s, 2H),
2.47 (m, 4H),
2.32 (m, 1H), 2.18 (m, 6H), 1.96 (m, 3H), 1.82 (m, 2H), 1.44 (m, 4H), 0.93 (s,
6H).
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EXAMPLE 224
4-(4- [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-y1]methyl )piperazin-l-
y1)-N-[(3-
nitro-4- [(3R)-1-(oxetan-3-yl)pyrrolidin-3-yflamino )phenyl)sulfony1)-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide
EXAMPLE 224A
(R)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate
The title compound was prepared by substituting (R)-tert-butyl pyrrolidin-3-
y1carbamate for tert-butyl piperazine-l-carboxylate and 3-oxetanone for 4'-
chlorobipheny1-2-
carboxaldehyde in EXAMPLE 1A.
EXAMPLE 224B
(R)-1-(oxetan-3-yl)pyrrolidin-3-amine
The title compound was prepared by substituting EXAMPLE 224A for (S)-1-tert-
butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate in EXAMPLE 168A.
EXAMPLE 224C
(R)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
nitrobenzenesulfonamide
for 4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 224B for 4-methylpiperazin-
1-
amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 224D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl] methyl } piperazin-
l-y1)-N- [(3-
nitro-4- { R3R)-1-(oxetan-3-yl)pyrrolidin-3-yllamino }phenyl)sulfony1]-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 224C for EXAMPLE
11B in EXAMPLE 11D. 11-1 NMR (400 MHz, pyridine-d5) 8 13.03 (s, 1H), 9.26 (d,
1H), 8.57
(d, 1H), 8.42 (d, 1H), 8.36 (dd, 1H), 8.09 (d, 11-1), 7.66 (m, 1H), 7.64 (d,
1H), 7.44 (m, 2H),
7.07 (m, 2H), 6.86 (d, 1H), 6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67
(m, 4H), 3.58 (m,
1H), 3.07 (m, 4H), 2.77 (m, 2H), 2.68 (m, 211), 2.61 (m, 1H), 2.28 (m, 4H),
2.14 (m, 4H),
1.97 (m, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 225
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-
y1)-N-1(4-
11(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yflaminol-3 -
Rtrifluoromethyl)sulfonyllphenyl)sulfony11-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 225A
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
To EXAMPLE 207A (0.217 g) and 4-fluoro-3-
(trifluoromethylsulfonyl)benzenesulfonamide (0.281 g) in tetrahydrofuran (5
mL) was added
diisopropylethylamine (0.559 mL) and the reaction was allowed to stir at room
temperature
for 1 hour and was then heated to 50 C for 1 hour. The reaction was
concentrated, the
residue was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient
of 0.75%
methanol/dichloromethane to 7.5% methanol/dichloromethane to provide the title
compound.
EXAMPLE 225B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-(1,3-difluoropropan-2-y1)pyrrolidin-3-yll amino1-3 -
Rtrifluoromethyl)sulfonyllphenyl)sulfony11-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 225A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.69 (s, 1H), 11.52 - 11.23 (m, 1H), 8.17 (d, 1H),
8.04 (d, 1H), 7.95
(d, 1H), 7.54 (d, 1H), 7.53 - 7.50 (m, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.10 -
6.97 (m, 4H),
6.67 (d, 1H), 6.40 (dd, 1H), 6.18 (d, 1H), 4.60 (dd, 4H), 4.20 (s, 1H), 3.11 -
2.63 (m, 12H),
2.19 (d, 6H), 1.95 (s, 2H), 1.58 (s, 1H), 1.40 (d, 2H), 0.92 (s, 6H).
EXAMPLE 226
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(1-isopropylpiperidin-4-yl)aminol -3 -nitrophenyllsulfony1)-2-(1H-pyrrolo12,3
-blpyridin-5-
yloxy)benzamide
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EXAMPLE 226A
tert-butyl 4-(4- (N-(2- (1H-pyrrolo12,3 -blpyridin-5 - yloxy)-4-(44(2- (4-
chloropheny0-4,4-
dimethylcyc lohex-1 -enyl)methyl)piperazin- 1- yl)benzoy0sulfamoyl) -2-
nitrophenylamino)piperidine- 1-c arboxyl ate
To a solution of EXAMPLE 82 (800 mg) and tert-butyl 4-aminopiperidine-1-
carboxylate (203 mg) in dioxane (10 mL) was added Hunig's Base (1 mL). The
mixture was
stirred at 120 C overnight. The mixture was diluted with ethyl acetate (200
mL) and washed
with water, brine and dried over Na2SO4. After filtration and evaporation of
solvent, the
residue was loaded on a silica gel cartridge and eluted with 3% methanol in
dichloromethane
to give the title compound.
EXAMPLE 226B
2-(1H-pyrrolo12,3 -blpyridin-5 -yloxy)-4- (44(2- (4-chloropheny0-4,4-
dimethylcyclohex- 1-
enyl)methyl)piperazin-1 -y1)-N- (3 -nitro-4-(piperidin-4- yl
amino)phenylsulfonyl)benzamide
To a solution of EXAMPLE 226A (902 mg) in dichloromethane (10 mL) was added
trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 3
hours. The
mixture was concentrated under vacuum and co-concentrated with dichloromethane
twice to
afford the crude product which was used in the next step without further
purification.
EXAMPLE 226C
4- (4-112-(4-chloropheny1)-4,4-dimethylcyclohex- 1-en-1 -yll methyllpiperazin-
1-y1)-N-(14-
1(1-is opropylpiperidin-4-yl)aminol -3 -nitrophenyllsulfony0-2-(1H-pyrrolo12,3
-blpyridin-5-
yloxy)benzamide
To a solution of EXAMPLE 226B (79 mg) in tetrahydrofuran (3 mL) and acetic
acid
(1 mL) was added acetone (54 mg) and MP-cyanoborohydride (150 mg, 2.25mmol/g).
The
mixture was stirred overnight. The mixture was filtered. The filtrate was
concentrated and the
residue was loaded on a silica gel cartridge and eluted with 5 to 10% 7N NH3
in methanol in
dichloromethane to provide the title compound. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8
12.09 (s, 1 H), 8.34 (m, 1 H), 7.93 (m, 2 H), 7.66 (m, 4 H), 7.35 (d, 2 H),
7.06 (d, 2 H), 6.89
(m, 1 H), 6.74 (dd, 1 H), 6.59 (dd, 1 H), 6.50 (d, 1 H), 3.11 (m, 6 H), 2.73
(m, 4 H), 2.26 (m,
9 H), 1.97 (s, 3 H), 1.40 (t, 2 H), 1.23 (s, 8 H), 0.94 (s, 6 H).
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EXAMPLE 227
N-(14-1(1-tert-butylpiperidin-4-yl)aminol -3-nitrophenyllsulfony1)-4- (4-112-
(4-chloropheny1)-
4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2- (1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
EXAMPLE 227A
1-tert-butylpiperidin-4-amine
To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100 mL) and
water
(10 mL) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The
mixture was
stirred overnight. The mixture was filtered and the filtrate was concentrated
under vacuum
and the residue was diluted with ethyl acetate (500 mL) and washed with water
and brine.
After drying over Na2SO4 and filtration, the solvent was evaporated under
vacuum to provide
the title compound.
EXAMPLE 227B
4-(1-tert-butylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
To a mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.2 g) and EXAMPLE 227A
(1.56 g) in tetrahydrofuran (20 mL) was added Hunig's Base (6 mL). The mixture
was stirred
for 3 days. The mixture was diluted with ethyl acetate (300 mL) and water (100
mL) and
stirred until the solid disappeared into the solution. The layers were
separated and the organic
phase was washed with water and brine, dried over Na2SO4, and filtered. The
combined
aqueous layers were extracted again with ethyl acetate and the combined
organic phases were
dried over Na2SO4. After filtration, the solvent was evaporated to provide the
title
compound.
EXAMPLE 227C
N-(14-1(1-tert-butylpiperidin-4-yl)aminol -3-nitrophenyllsulfony1)-4- (4-112-
(4-chloropheny1)-
4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2- (1H-pyrrolo12,3 -
blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 227B for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.51 (s, 1 H), 8.43 (d, 1 H), 8.04 (m, 1 H), 7.93 (d,
1 H), 7.72 (m, 1
H), 7.56 (dd, 1 H), 7.42 (m, 1 H), 7.34 (m, 3 H), 7.05 (d, 2 H), 6.93 (dd, 1
H), 6.62 (dd, 1 H),
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6.28 (m, 1 H), 3.04 (m, 6 H), 2.73 (s, 3 H), 2.25 (m, 9 H), 1.95 (s, 2 H),
1.68 (m, 2 H), 1.32
(m, 9 H), 0.93 (s, 6 H).
EXAMPLE 228
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ 114-
({ [1-(2-methoxyethyl)piperidin-3-yl[methyl}amino)-3-nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 228A
tert-butyl 3-((2-nitro-4-sulfamoylphenylamino)methyl)piperidine-1-carboxylate
The title compound was prepared by substituting tert-butyl 3-
(aminomethyl)piperidine-1-carboxylate for (tetrahydropyran-4-yl)methylamine in

EXAMPLE 1F.
EXAMPLE 228B
3-nitro-4-(piperidin-3-ylmethylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 228A for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 228C
4-((1-(2-methoxyethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 228B for EXAMPLE
134A and 2-methoxyethyl bromide for methyl iodide in EXAMPLE 134B.
EXAMPLE 228D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-{ [4-
( { [1-(2-methoxyethyl)piperidin-3-yl[methyl}amino)-3-nitrophenyl[sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 228C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5, 90 C) 8 12.40 (s, 1H),
8.52 (s,
1H), 8.43 (s, 1H), 8.20 (m, 2H),7.95 (bs, 1H), 7.80 (s, 1H), 7.46 (d, 1H),
7.36 (d, 2H), 7.07
(d, 2H), 7.05 (s, 1H), 6.75 (d, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.65-3.50 (m,
5H),3.20 (s, 3H),
3.04 (m, 5H), 2.81 (s, 3H), 2.74 (m, 1H), 2.24 (m, 7H), 2.06 (s, 2H), 2.00 (s,
2H), 1.75 (m,
1H), 1.57 (m, 2H), 1.42 (t, 2H), 1.15 (m, 1H), 0.95 (s, 6H).
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EXAMPLE 229
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-114-
(111-(c yanomethyl)piperidin-3-yll methyllamino)-3 -nitrophenyll sulfony11-2-
(1H-pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 229A
4-((1-(cyanomethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 228B for EXAMPLE
134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.
EXAMPLE 229B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-114-
(111-(c yanomethyl)piperidin-3-yll methyllamino)-3 -nitrophenyll sulfony11-2-
(1H-pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 229A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.06 (s, 1H), 9.03 (s,
1H),
8.42 (s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.68 (m, 2H), 7.44 (d, 2H), 7.08 (m,
3H), 6.99 (d,
1H), 6.75 (d, 1H), 6.51 (m, 2H), 3.78 (m, 2H), 3.43 (d, 1H), 3.13 (m, 1H),
3.04 (m, 4H), 2.76
(s, 2H), 2.71-2.65 (m, 3H), 2.52 (m, 1H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.84 (m,
1H), 1.68 (m, 1H), 1.50 (m, 2H), 1.39 (t, 2H), 1.07-0.99 (m, 1H), 0.93 (s,
6H).
EXAMPLE 230
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(14-
1(4-fluoro-1-methylpiperidin-4-yl)methoxyl -3-
Rtrifluoromethyl)sulfonyllphenyllsulfony1)-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 230A
4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.315 g) in
tetrahydrofuran (5 mL) was added sodium hydride (0.342 g). After stifling for
15 minutes, 4-
fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.658 g) was added as a
solution in
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tetrahydrofuran (2 mL) followed by additional tetrahydrofuran (5 mL). After
stirring for 1
hour, the reaction was poured in dichloromethane (50 mL) and water (25 mL) and
the pH of
the water layer was adjusted to 8. The organic layer was dried over magnesium
sulfate,
filtered, and concentrated. The resulting oil was chromatographed over silica
gel (Reveleris
40 g) eluting with a gradient of 1.0% to 10% 7N NH3 in
methanol/dichloromethane over 20
minutes then maintaining 10% 7N NH3 in methanol/dichloromethane for 5 minutes
(flow =
30 mL/min) to provide the title compound.
EXAMPLE 230B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 4-
R4-fluoro-1-methylpiperidin-4-yl)methoxyl -3- Rtrifluoromethyl)sulfonyllphenyl
I sulfony1)-2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 230A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 6 11.63 - 11.57 (m, 1H), 8.40 - 8.36 (m, 1H), 8.28 -
8.17 (m, 1H), 7.97
(s, 1H), 7.53 (d, 1H), 7.50 - 7.32 (m, 5H), 7.05 (d, 1H), 7.05 (d, 1H), 6.68 -
6.61 (m, 1H),
6.35 (s, 1H), 6.22 (s, 1H), 4.55 - 4.40 (m, 2H), 3.06 (s, 8H), 2.79 (s, 4H),
2.06 (d, 13H), 1.39
(s, 2H), 0.93 (s, 6H).
EXAMPLE 231
N- R5 -chloro-6- { R3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yll amino I
pyridin-3 -
yl)sulfonyll-4-(4- { l2-(4-chloropheny1)-4,4-dimethylc yclohex-1-en-l-yll
methyl } piperazin-l-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 231A
(R)-5-chloro-6-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)pyridine-3-
sulfonamide
To EXAMPLE 207A (0.051 g) and EXAMPLE 40A (0.049 g) in dioxane (5 mL) was
added diisopropylethylamine (0.131 mL) and the reaction was heated to 75 C for
1 hour then
85 C for 2 days. The reaction was concentrated, loaded onto silica gel
(Reveleris 12 g) and
eluted with a gradient of 0.75% methanol/dichloromethane to 7.5%
methanol/dichloromethane to provide the title compound.
EXAMPLE 231B
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N- 11(5 -chloro-6- I R3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yll
aminolpyridin-3-
yl)sulfonyll-4-(4- I 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-
y1)-2-(1H-pyrrolo112,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 231A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.71 (s, 1H), 11.44 - 11.11 (m, 1H), 8.44 (d, 1H),
8.07 (d, 1H), 7.90
(d, 1H), 7.61 (d, 1H), 7.52 (dd, 2H), 7.34 (d, 2H), 7.19 (s, 1H), 7.04 (d,
2H), 6.67 (d, 1H),
6.42 (dd, 1H), 6.16 (s, 1H), 4.77 - 4.39 (m, 5H), 3.19 - 2.63 (m, 11H), 2.19
(s, 7H), 1.91 (d,
3H), 1.38 (s, 2H), 0.92 (s, 6H).
EXAMPLE 232
tert-butyl 4-11(4-{ [4-(4-{ 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yll methyl}piperazin-l-y1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -yloxy)benzoyll
sulfamoy11-2-
nitrophenyBaminolpiperazine-l-carboxylate
EXAMPLE 232A
tert-butyl 4-nitrosopiperazine-1-carboxylate
In a 500 mL round-bottomed flask, 6N aqueous HC1 (30 mL) was cooled to -10 C,

and tert-butyl piperazine-l-carboxylate (10 g) was added. Sodium nitrite (4.5
g) dissolved in
35 ml water was added slowly. NaOH (10 g in 20 mL water) was used to
neutralize the
solution. Dichloromethane (3x 50 mL) was used to extract the product. After
drying over
Na2SO4 and filtration, the solution was concentrated. The crude product was
added to a silica
gel column (Analogix, SF65-400 g,) and purified by eluting with 0-30% ethyl
acetate in
hexane.
EXAMPLE 232B
tert-butyl 4-aminopiperazine-1-carboxylate
In a 100 mL round-bottomed flask was added EXAMPLE 232A (0.15 g) and zinc (1
g) in water/methanol (1:1, 10 mL) to give a suspension. The mixture was cooled
to 0 C. 12N
Aqueous HC1 (2 ml) was added slowly, and the mixture was stirred at 0 C for
30 minutes.
2N Aqueous NaOH solution was used to adjust the mixture to basic pH. The
mixture was
filtered, and extracted with ether (3x 30 mL). After drying over Na2504,
filtration, and
concentration, the crude product was added to a silica gel column ( Analogix,
5F15-12g,) and
purified by eluting with 0-25% ethyl acetate in hexane.
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EXAMPLE 232C
tert-butyl 4-(2-nitro-4-sulfamoylphenylamino)piperazine-1-carboxylate
The title compound was prepared by substituting EXAMPLE 232B for 1-
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 232D
tert-butyl 4-1(4-114-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-y1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzoyll
sulfamoy11-2-
nitrophenyBaminolpiperazine-l-carboxylate
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 232C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.47 (br. s, 1H), 8.86 (s, 1H), 8.34 (d, 1H), 7.90
(d, 1H), 7.59 (m,
2H), 7.36 (m, 4H), 7.23 (m, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.27 (m, 2H),
2.99 (m, 5H),
2.76 (m, 6H), 2.19 (m, 6H), 1.96 (s, 2H), 1.41 (m, 11H), 1.24 (m, 4H), 0.93
(s, 6H).
EXAMPLE 233
4- (4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-1-
y1)-N-(13-
(pentafluoro-lambda-6--sulfany1)-4-1(tetrahydro-2H-pyran-4-
ylmethyl)aminolphenyllsulfony1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 233A
2-(5-bromo-2-nitrophenyl)sulfur pentafluoride
To a solution of 3-bromophenylsulfur pentafluoride (2.18 g) in concentrated
H2SO4 (5
mL) was added KNO3 (780 mg). The mixture was stirred overnight. The mixture
was
diluted with diethyl ether (100 mL) and washed with water and brine. After
drying over
Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the
title
compound.
EXAMPLE 233B
2-(5-bromo-2-aminophenyl)sulfur pentafluoride
EXAMPLE 233A (6.4g) and tetrahydrofuran (300 mL) were added to Ra-Ni, (12.80
g) in a 50 mL pressure bottle and the mixture stirred for 2 hours at 30 psi
and room
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temperature. The mixture was filtered though a nylon membrane and the filtrate
was
concentrated under vacuum to provide the title compound.
EXAMPLE 233C
4-bromo-2-pentafluorosulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)aniline
To a solution of EXAMPLE 233B (4.4 g) in methanol (50 mL) was added tetrahydro-

2H-pyran-4-carbaldehyde (1.68 g) and decaborane (1.1 g). The mixture was
stirred and
monitored by thin layer chromatography. More tetrahydro-2H-pyran-4-
carbaldehyde (500
mg) was added to the stirring mixture to drive the reaction to completion. The
reaction
mixture was concentrated under vacuum and ethyl acetate (500 mL) and brine
(200 mL) were
added. The organic phase was dried over Na2SO4. Filtration and evaporation of
the solvent
and flash chromatography (20% ethyl acetate in hexane) gave the title
compound.
EXAMPLE 233D
4-thioacetoxy-2-pentafluorosulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)aniline
To a solution of EXAMPLE 233C (456 mg) and potassium ethanethioate (197 mg) in

dioxane (4 mL) was added tris(dibenzylideneacetone)dipalladium(0) (27 mg) and
xantphos
(33 mg) followed by N,N-diisopropylethylamine (0.5 mL). The mixture was purged
with
argon, sealed and stirred under microwave irradiation for 60 minutes at 120 C.
The mixture
was dissolved in ethyl acetate (300 mL) and water (100 mL). The organic phase
was washed
with brine and dried over Na2SO4. Filtration and evaporation of the solvent
followed by flash
chromatography (20% ethyl acetate in hexane) provided the title compound.
EXAMPLE 233E
3-pentafluorosulfany1-4-Rtetrahydro-2H-pyran-4-
ylmethyl)aminolphenylsulfonamide
N-chlorosuccinimide (527 mg) was added to a mixture of 2N aqueous HC1 (1.5 mL)
and acetonitrile (12 mL) and then cooled to 0 C. A solution of EXAMPLE 233D
(386 mg) in
acetonitrile (3 mL) was added to the mixture which was then stirred at 0 C for
2 hours, and
then diluted with ethyl acetate (300 mL) and washed with brine and dried over
Na2SO4. After
filtration and evaporation of solvent, the residue was dissolved in isopropyl
alcohol (20 mL)
and cooled to 0 C with stirring. Then, ammonium hydroxide (conc. 10 mL) was
added to
mixture. After stifling for 2 hours, the mixture was concentrated under vacuum
and the
residue was added to ethyl acetate (400 mL) and water (150 mL). The organic
layer was
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washed with brine and dried over Na2SO4. After filtration and evaporation of
solvent, the
residue was purified by flash column ( 20% ethyl acetate in dichloromethane)
to provide the
title compound.
EXAMPLE 233F
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
(pentafluoro-lambda-6--sulfany1)-4-1(tetrahydro-2H-pyran-4-
ylmethyBaminolphenyllsulfony1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 233E for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.71 (s, 1 H), 11.33 (m, 1 H), 8.12 (m, 2 H), 7.72
(d, 1 H), 7.54
(m, 3 H), 7.33 (m, 2 H), 7.02 (m, 3 H), 6.67 (m, 2 H), 6.42 (m, 1 H), 6.16 (d,
1 H), 3.82 (m, 2
H), 3.21 (m, 4 H), 3.05 (m, 4 H), 2.73 (s, 2 H), 2.21 (m, 8 H), 1.97 (m, 3 H),
1.29 (m, 4 H),
0.92 (s, 6 H).
EXAMPLE 234
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(4-methoxytetrahydro-2H-pyran-4-y1)methoxyl -3-nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 234A
4-vinyltetrahydro-2H-pyran-4-ol
Dihydro-2H-pyran-4(3H)-one (8.01 g) in anhydrous ethyl ether (50 mL) was
treated
with 1.0 M vinylmagnesium bromide (104 mL) over 20 minutes at 0 C. The
reaction mixture
was stirred at room temperature overnight. The reaction was quenched with
saturated NH4C1,
and the organic layer was separated. The aqueous layer was extracted with
additional ethyl
ether three times. The combined organic layers were washed with brine, dried,
filtered, and
concentrated. The residue was purified by flash column chromatography on
silica gel using
20% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 234B
4-methoxy-4-vinyltetrahydro-2H-pyran
To a solution of EXAMPLE 234A (9.4 g) in tetrahydrofuran (150 mL) was added 60

% sodium hydride (5.28 g) at 0 C portionwise. After the addition was complete,
the solution
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was heated under reflux for three hours. After cooling, to this suspension was
added dimethyl
sulfate (8.41 mL) slowly. The solution was heated under reflux overnight,
cooled to room
temperature, and hydrolyzed with cool saturated aqueous NH4C1. After
extraction with
diethyl ether several times, the combined organic layers were washed with
brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by flash column
chromatograph
on silica gel using 1-10% ethyl acetate in hexanes to provide the title
compound.
EXAMPLE 234C
4-methoxytetrahydro-2H-pyran-4-carbaldehyde
EXAMPLE 234B (4.3 g) in tetrahydrofuran (200 mL) and water (67 mL) was treated
with 4% osmium tetroxide in water (9.24 mL). To this solution was added
potassium
periodate (13.91 g) portionwise over 2 hours. The solution was stirred
overnight at room
temperature. Water was added to the mixture followed by repeat extractions
with diethyl
ether. The combined organic layers were dried over MgSO4, filtered, and
concentrated. The
residue was purified by flash column chromatography on silica gel using 5-20%
ethyl acetate
in hexanes to provide the title compound.
EXAMPLE 234D
(4-methoxytetrahydro-2H-pyran-4-yl)methanol
EXAMPLE 234C (1.8 g) in 2-propanol (28 mL) and water (7 mL) was cooled to 0
C.
To this solution was added sodium borohydride (0.709 g). The solution was
stirred and
allowed to warm to room temperature over 3 hours. The reaction was quenched
with acetone,
and stirred for another 1 hour. The clear liquid was separated from solid by
decanting.
Additional ethyl acetate was used to wash the solid, and was the mixture was
decanted. The
combined organic solutions were concentrated. The residue was purified by
flash
chromatography on silica gel eluting 1:1 ethyl acetate: hexane to provide the
title compound.
EXAMPLE 234E
4-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 234D for (tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 234F
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4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(14-
1(4-methoxytetrahydro-2H-pyran-4-y1)methoxyl -3-nitrophenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 234E for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.68 (s,
1H), 8.36 (s, 1H), 8.04-8.07 (m, 2H), 7.50-7.53 (m, 3H), 7.45 (d, 1H), 7.35
(d, 2H), 7.05 (d,
2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.21 (s, 2H), 3.65-3.67 (m,
2H), 3.53-3.56
(m, 2H), 3.19 (s, 3H), 3.10 (s, 4H), 2.86 (s, 2H), 2.30 (s, 4H), 2.15 (s, 2H),
1.96 (s, 2H), 1.61-
1.74 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 235
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(3R)-1-(1,3-difluoropropan-2-y1)pyrrolidin-3-ylloxyl-3-nitrophenyl)sulfonyll-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 235A
(R)-tert-butyl 3-(2-nitro-4-sulfamoylphenoxy)pyrrolidine-1-carboxylate
The title compound was prepared by substituting (R)-tert-butyl 3-
hydroxypyrrolidine-
1-carboxylate for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 235B
(R)-te rt-butyl 3-(4-(N-(2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
nitrophenoxy)pyrrolidine-1-carboxylate
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 235A for EXAMPLE 1F in EXAMPLE 1G.
EXAMPLE 235C
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-
y1)-N-1(4-
11(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylloxy1-3-nitrophenyl)sulfonyll-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
To a solution of EXAMPLE 235B (0.230 g) in dichloromethane (3 mL) was added
trifluoroacetic acid (0.377 mL). After stirring for 4 hours, the reaction was
concentrated then
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dissolved in dichloromethane (3 mL) and treated with 1,3-difluoropropan-2-one
(0.028 g)
followed by sodium triacetoxyborohydride (0.078 g). After stirring for 4
hours, the reaction
was quenched by the addition of saturated aqueous NaHCO3and dichloromethane (5
mL).
The reaction was diluted with dichloromethane (250 mL) and saturated aqueous
NaHCO3
(100 mL) was added. The organic layer was separated, washed with brine (100
mL), dried
over magnesium sulfate, filtered and concentrated. Trituration with
acetonitrile gave the title
compound. 1H NMR (300 MHz, dimethylsulfoxide- d6) 6 11.67 (s, 1H), 8.34 (s,
1H), 8.03 (s,
2H), 7.52 (d, 3H), 7.35 (d, 3H), 7.04 (d, 2H), 6.75 - 6.60 (m, 1H), 6.40 (s,
1H), 6.20 (s, 1H),
5.17 - 5.06 (m, 1H), 4.60 (d, 4H), 2.98 (d, 12H), 2.37 - 2.02 (m, 6H), 1.96
(s, 3H), 1.39 (s,
2H), 0.93 (s, 6H).
EXAMPLE 236
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { 1L4-(oxetan-3-yl)piperazin-1-yll amino } phenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -blpyridin-
5-yloxy)benzamide
EXAMPLE 236A
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(3-nitro-4-(piperazin-1-
ylamino)phenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 232D for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 236B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { [4-(oxetan-3-yl)piperazin-1-yll amino } phenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -blpyridin-
5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 236A for tert-butyl
piperazine-l-carboxylate and oxetan-3-one for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.67 (br. s, 1H), 9.20
(s, 1H),
8.53 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H), 7.53 (m, 4H), 7.34 (d, 2H), 7.04
(d, 2H), 6.67 (dd,
1H), 6.39 (m, 1H), 6.18 (d, 1H), 4.55 (t, 2H), 4.44 (t, 2H), 3.47 (m, 1H),
3.06 (m, 4H), 2.88
(m, 4H), 2.74 (m, 4H), 2.09 (m, 11H), 1.38 (t, 2H), 0.91 (s, 6H).
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EXAMPLE 237
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- R3 -
nitro-4- { [4-(tetrahydro-2H-pyran-4-y0piperazin-1-yll amino }
phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 236A for tert-butyl
piperazine-l-carboxylate and dihydro-2H-pyran-4(3H)-one for 4'-chlorobipheny1-
2-
carboxaldehyde in EXAMPLE 1A. 1H NMR (400 MHz, pyridine-d5) 6 13.05 (br. s,
1H),
9.27 (d, 1H), 9.23 (s, 1H), 8.44 (m, 2H), 8.12 (d, 1H), 7.68 (m, 3H), 7.44 (m,
2H), 7.06 (m,
2H), 6.75 (dd, 1H), 6.51 (m, 2H), 4.02 (m, 2H), 3.31 (m, 2H), 3.06 (m, 4H),
2.91 (m, 5H),
2.76 (s, 2H), 2.38 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.65 (m,
2H), 1.39 (m,
7H), 0.93 (s, 6H).
EXAMPLE 238
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R3R)-tetrahydrofuran-3-ylaminolphenyl } sulfony0-2-(1H-pyrrolo [2,3 -
blpyridin-5 -
yloxy)benzamide
EXAMPLE 238A
(R)-3-nitro-4-(tetrahydrofuran-3-ylamino)benzenesulfonamide
The title compound was prepared by substituting (R)-tetrahydrofuran-3-amine
for 4-
methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 238B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- R3R)-tetrahydrofuran-3-ylaminolphenyl } sulfony0-2-(1H-pyrrolo [2,3 -
blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 238A for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (400 MHz,
dimethylsulfoxide-d6) 8 11.59 (s, 1H), 8.47 (d, 1H), 8.19 (m, 2H), 7.97 (d,
1H), 7.74 (m,
1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.34 (m, 2H), 7.05 (m, 2H), 6.96 (d, 1H),
6.89 (d, 1H), 6.65
(dd, 1H), 6.33 (m, 1H), 6.22 (d, 1H), 4.31 (m, 1H), 3.92 (m, 1H), 3.87 (m,
1H), 3.76 (m, 1H),
3.69 (m, 1H), 3.04 (m, 4H), 2.73 (m, 2H), 2.33 (m, 1H), 2.18 (m, 6H), 1.95 (m,
2H), 1.88 (m,
1H), 1.39 (t, 2H), 0.92 (s, 6H).
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EXAMPLE 239
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ R4,4-difluorocyclohexyl)methyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 239A
tert-butyl (4,4-difluorocyclohexyl)methylcarbamate
Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) and diethylaminosulfur
trifluoride
(7.45 g) were stirred in dichloromethane (100 mL) for 24 hours. The mixture
was quenched
with pH 7 buffer (100 mL), and poured into ether (400 mL). The resulting
solution was
separated, and the organic layer was washed twice with water, and once with
brine, and then
concentrated to give the crude product and fluoroolefin by-product in a 3:2
ratio. The crude
material was taken up in tetrahydrofuran (70 mL) and water (30 mL), and N-
methylmorpholine-N-oxide (1.75 g), and 0s04 (2.5 wt % solution in t-butanol)
were added,
and the mixture was stirred for 24 hours. Na2S203 (10 g) was then added, and
the mixture
was stirred for 30 minutes. The mixture was then diluted with ether (300 mL),
and the
resulting solution was separated, and rinsed twice with water, and once with
brine, and
concentrated. The crude product was chromatographed on silica gel using 5-10%
ethyl
acetate in hexanes to provide the title compound.
EXAMPLE 239B
(4,4-difluorocyclohexyl)methanamine
A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL), trifluoroacetic
acid
(15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was
concentrated,
then concentrated from toluene, and left on high vacuum for 24 hours. The semi-
solid was
taken up in ether/hexane and filtered to provide the title compound as its
trifluoroacetic acid
salt.
EXAMPLE 239C
4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 239B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
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EXAMPLE 239D
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(4,4-difluorocyclohexyl)methyllaminol-3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 239C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 12.40 (s, 1H), 11.61 (br s, 1H), 8.53 (m, 1H), 8.50
(d, 1H), 7.99 (d,
1H), 7.73 (d, 1H), 7.49 (m, 2H), 7.32 (d, 2H), 7.04 (d, 2H), 7.00 (d, 1H),
6.65 (d, 1H), 6.32
(s, 1H), 6.21 (s, 1H), 3.37 (m, 4H), 3.06 (m, 4H), 2.73 (m, 2H), 2.18 (m, 4H),
1.97 (m, 4H),
1.81 (m, 4H), 1.38 (m, 2H), 1.20 (m, 4H), 0.92 (s, 6H).
EXAMPLE 240
N-(14- R1-tert-butylpiperidin-4-yl)aminol -3 -
Rtrifluoromethyl)sulfonyllphenyllsulfony1)-4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 240A
4-(1-tert-butylpiperidin-4-ylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide
To a mixture of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (307
mg)
and EXAMPLE 227A (156 mg) in tetrahydrofuran (4 mL) was added Hunig's Base (1
mL).
The mixture was stirred for 3 days. The mixture was diluted with ethyl acetate
(300 mL) and
water (100 mL) and stirred until the solid disappeared into the solution. The
layers were
separated and the organic phase was washed with water, brine and dried over
Na2SO4. After
filtration, the combined aqueous layers were extracted again with ethyl
acetate and the
combined organic phase was dried over Na2SO4. After filtration, the solvent
was evaporated
to provide the title compound.
EXAMPLE 240B
N-(14- R1-tert-butylpiperidin-4-yl)aminol -3 -
Rtrifluoromethyl)sulfonyllphenyllsulfony1)-4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 240A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
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dimethylsulfoxide-d6) 8 11.53 (s, 1 H), 8.04 (s, 1 H), 7.94 (d, 1 H), 7.86 (m,
1 H), 7.55 (d, 2
H), 7.44 (d, 1 H), 7.33 (m, 3 H), 7.05 (d, 2 H), 6.92 (m, 1 H), 6.62 (dd, 1
H), 6.43 (m, 1 H),
6.29 (d, 2 H), 3.79 (m, 1 H), 3.05 (m, 6 H), 2.73 (s, 3 H), 2.19 (m, 8 H),
1.96 (s, 3 H), 1.27
(m, 12 H), 0.92 (s, 6 H).
EXAMPLE 241
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N-( { 4-
( { [4-(oxetan-3 -yl)morpholin-2-yll methyl } amino)-3 -
Rtrifluoromethyl)sulfonyll phenyl I sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -
yloxy)benzamide
EXAMPLE 241A
tert-butyl 2-((4-sulfamoy1-2-
(trifluoromethylsulfonyl)phenylamino)methyl)morpholine-4-
carboxylate
The title compound was prepared by substituting tert-butyl 2-
(aminomethyl)morpholine-4-carboxylate for (tetrahydropyran-4-yl)methylamine
and 4-
fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 1F.
EXAMPLE 241B
tert-butyl 2-((4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
(trifluoromethylsulfonyl)phenylamino)methyl)morpholine-4-carboxylate
The title compound was prepared by substituting EXAMPLE 241A for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G.
EXAMPLE 241C
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)-N-(4-(morpholin-2-ylmethylamino)-3-
(trifluoromethylsulfonyl)phenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 241B for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 241D
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4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(14-
(1 1L4-(oxetan-3-yl)morpholin-2-yllmethyl I amino)-3-
Rtrifluoromethyl)sulfonyllphenyl I sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 241C for tert-butyl
piperazine-l-carboxylate and oxetan-3-one for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 8.15 (d,
1H),
8.04 (d, 1H), 7.92 (dd, 1H), 7.54 (d, 1H), 7.51 (t, 1H), 7.48 (d, 1H), 7.34
(d, 2H), 7.25 (m,
1H), 7.04 (m, 3H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.19 (d, 1H), 4.54 (t, 2H),
4.43 (m, 2H), 3.85
(m, 1H), 3.69 (m, 1H), 3.52 (m, 1H), 3.48 (m, 1H), 3.39 (m, 2H), 3.07 (m, 4H),
2.77 (br s,
2H), 2.69 (d, 1H), 2.56 (d, 1H), 2.21 (br s, 4H), 2.15 (t, 2H), 1.94 (m, 3H),
1.76 (t, 1H), 1.38
(t, 2H), 0.92 (s, 6H).
EXAMPLE 242
N-R5-chloro-6- { R4-fluorotetrahydro-2H-pyran-4-yl)methyll amino } pyridin-3-
yl)sulfonyll -4-
(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 242A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 138D.
EXAMPLE 242B
N-R5-chloro-6- { R4-fluorotetrahydro-2H-pyran-4-yl)methyll amino } pyridin-3-
yl)sulfonyll -4-
(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 242A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.71 (s,
1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.51-7.53 (m,
2H), 7.40 (s, 1H),
7.33-7.35 (m, 2H), 7.03-7.05 (m, 2H), 6.68 (dd, 1H), 6.42 (dd, 1H), 6.16 (d,
1H), 3.77 (d,
1H), 3.69-3.71 (m, 3H), 3.48-3.53 (m, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.14-
2.20 (m, 6H),1.96
(s, 2H), 1.65-1.76 (m, 4H), 1.38 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 243
N-(15-chloro-6-1(1-cyclopropylpiperidin-4-yl)aminolpyridin-3-yllsulfony1)-4-(4-
112-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-l-yllmethyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 243A
5-chloro-6-(1-cyclopropylpiperidin-4-ylamino)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-chloro-3-
nitrobenzenesulfonamide, 1-cyclopropylpiperidin-4-amine for 4-methylpiperazin-
1-amine
dihydrochloride and Hunig's base for N1,N1,N2,N2-tetramethylethane-1,2-diamine
in
EXAMPLE 6A.
EXAMPLE 243B
N-(15-chloro-6-1(1-cyclopropylpiperidin-4-yl)aminolpyridin-3-yllsulfony1)-4-(4-
112-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 243A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1H),
8.40 (d,
1H), 8.05 (d, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.50 (m, 2H), 7.34 (d, 2H),
7.03 (d, 2H), 6.97
(br d, 1H), 6.66 (dd, 1H), 6.40 (m, 1H), 6.16 (d, 1H), 4.04 (m, 1H), 3.03 (br
m, 6H), 2.73 (s,
2H), 2.42 (br m, 2H), 2.18 (br m, 6H), 1.95 (s, 2H), 1.80 (m, 3H), 1.62 (m ,
2H), 1.38 (t, 2H),
0.91 (s, 6H), 0.47 (m, 2H), 0.40 (br m, 2H).
EXAMPLE 244
N-1(5-chloro-6-11(2S)-4-(cyanomethyl)morpholin-2-yllmethoxylpyridin-3-
yl)sulfonyll-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-yllmethyllpiperazin-l-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 244A
(S)-tert-butyl 2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-
carboxylate
The title compound was prepared by substituting (S)-tert-butyl 2-
(hydroxymethyl)-
morpholine-4-carboxylate for tetrahydro-2H-pyran-4-yl-methanol and EXAMPLE 40A
for 4-
fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
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EXAMPLE 244B
(S)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 244A for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 244C
(S)-5-chloro-6-((4-(cyanomethyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 244B for EXAMPLE
134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.
EXAMPLE 244D
N-R5-chloro-6- { R2S)-4-(cyanomethyl)morpholin-2-yllmethoxylpyridin-3-
yl)sulfonyll-4-(4-
{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 244C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 12.99 (s, 1H), 9.09 (d,
1H),
8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d,
2H), 6.75 (dd,
1H), 6.53 (d, 1H), 6.48 (m, 1H), 4.55 (dd, 1H),4.43 (dd, 1H), 4.05 (m, 1H),
3.85 (d, 1H), 3.76
(s, 2H), 3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58 (d,
1H), 2.51-2.44 (m,
2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 245
N- R5 -chloro-6- { R2S)-4-(N,N-dimethylglycyl)morpholin-2-yllmethoxylpyridin-3-

yl)sulfonyll -4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 245A
(S)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 244B for EXAMPLE
134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyl iodide in
EXAMPLE
134B.
EXAMPLE 245B
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N- R5 -chloro-6- { 11(2S)-4-(N,N-dimethylglycyl)morpholin-2-yllmethoxy I
pyridin-3-
yl)sulfonyll -4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl } piperazin-1-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 245A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.09 (d,
1H),
8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d,
2H), 6.76 (s, 1H),
6.54 (s, 1H), 6.49 (s, 1H), 4.85-4.46 (m, 3H),4.45-3.87 (m, 3H), 3.50 (m, 1H),
3.37 (dd, 1H),
3.21 (m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m, 8H), 2.14 (m,
4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 246
N-R5-chloro-6- { R2R)-4-(cyanomethyl)morpholin-2-yllmethoxy lpyridin-3-
yl)sulfonyll-4-(4-
{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 246A
(R)-tert-butyl 2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-
carboxylate
The title compound was prepared by substituting (R)-tert-butyl 2-
(hydroxymethyl)-
morpholine-4-carboxylate for tetrahydro-2H-pyran-4-yl-methanol and EXAMPLE 40A
for 4-
fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 246B
(R)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 246A for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 246C
(R)-5-chloro-6-((4-(cyanomethyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 246B for EXAMPLE
134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.
EXAMPLE 246D
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N-R5-chloro-6- { R2R)-4-(cyanomethyl)morpholin-2-yllmethoxy lpyridin-3-
yl)sulfony11-4-(4-
{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 246C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 12.99 (s, 1H), 9.09 (d,
1H),
8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d,
2H), 6.75 (dd,
1H), 6.53 (d, 1H), 6.48 (m, 1H), 4.55 (dd, 1H),4.43 (dd, 1H), 4.05 (m, 1H),
3.85 (d, 1H), 3.76
(s, 2H), 3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58 (d,
1H), 2.51-2.44 (m,
2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 247
N-R5-chloro-6-{ R2R)-4-(N,N-dimethylglycyl)morpholin-2-yllmethoxy lpyridin-3-
yl)sulfony11-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 247A
(R)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 246B for EXAMPLE
134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyl iodide in
EXAMPLE
134B.
EXAMPLE 247B
N-R5-chloro-6-{ R2R)-4-(N,N-dimethylglycyl)morpholin-2-yllmethoxy lpyridin-3-
yl)sulfonyll-4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyl}piperazin-1-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 247A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.09 (d,
1H),
8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d,
2H), 6.76 (s, 1H),
6.54 (s, 1H), 6.49 (s, 1H), 4.85-4.46 (m, 3H),4.45-3.87 (m, 3H), 3.50 (m, 1H),
3.37 (dd, 1H),
3.21 (m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m, 8H), 2.14 (m,
4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
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EXAMPLE 248
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(15-
fluoro-6-1(4-fluorotetrahydro-2H-pyran-4-y1)methoxylpyridin-3-yllsulfony0-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 248A
5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine
The title compound was prepared by substituting 5-bromo-2,3-difluoropyridine
for 4-
fluoro-3-nitrobenzenesulfonamide and EXAMPLE 37C for (tetrahydro-2H-pyran-4-
yl)methanol in EXAMPLE 24A.
EXAMPLE 248B
tert-butyl 5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-
ylcarbamate
EXAMPLE 248A (0.308 g), tert-butyl carbamate (0.141 g), palladium(II) acetate
(0.011 g), Xantphos (0.043 g) and cesium carbonate (0.489 g) were combined
with dioxane
(5.0 mL) in a 20-mL vial equipped with a magnetic stir bar. The vial was
flushed with
nitrogen, capped and stirred at 100 C overnight. Additional palladium(II)
acetate (0.011 g),
Xantphos (0.043 g) and tert-butyl carbamate (0.141 g) were added and heating
was continued
at 100 C for 8 hours. The cooled reaction mixture was diluted with ethyl
acetate, washed
with water and brine, dried (Mg504), filtered and concentrated. The
concentrate was
chromatographed on silica gel with 7-25% ethyl acetate in hexanes as the
eluent.
EXAMPLE 248C
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl
chloride
Under ice-cooling, thionyl chloride (1.563 mL) was added dropwise over 20
minutes
to water (9 mL). The mixture was stirred for 12 hours to give a 502-containing
solution.
Separately, EXAMPLE 248B (0.295 g) was added to a mixture of 1,4-dioxane (3.2
mL) and
concentrated HC1 (8 mL) at 0 C. After stirring for 15 minutes, a solution of
sodium nitrite
(0.065 g) in water (2 mL) was added dropwise and stirring was continued at 0 C
for 3 hours.
Copper(I) chloride (0.042 g) and then the freshly prepared solution of
diazotized material
were added sequentially to the previously prepared 502-containing solution.
The resulting
solution was stirred for 30 minutes and then extracted with ethyl acetate (2 x
125 mL). The
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combined extracts were dried (MgSO4), filtered and concentrated. The
concentrate was
chromatographed on silica gel with 5% ethyl acetate in hexanes as the eluent.
EXAMPLE 248D
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
EXAMPLE 248C (0.08 g) in isopropanol (2 mL) at 0 C was treated with ammonium
hydroxide (1.697 mL), stirred overnight and then concentrated to dryness. The
obtained solid
was slurried in water, filtered, rinsed with water and dried under high vacuum
to provide the
title compound.
EXAMPLE 248E
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(15-
fluoro-6-1(4-fluorotetrahydro-2H-pyran-4-y1)methoxylpyridin-3-yllsulfony1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 248D for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.05 (s, 1H), 9.03 (d,
1H), 8.44
(dd, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.67 (m, 1H), 7.65 (d, 1H), 7.44 (m,
2H), 7.07 (m, 2H),
6.77 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 4.55 (d, 2H), 3.80 (m, 4H), 3.08
(m, 4H), 2.77 (s,
2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.88 (m, 4H), 1.39 (t, 2H),
0.94 (s, 6H).
EXAMPLE 250
N-(15-chloro-6-13-hydroxy-2-(hydroxymethyl)-2-methylpropoxylpyridin-3-
yllsulfony1)-4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 250A
5-chloro-6-((3-methyloxetan-3-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting (3-methyloxetan-3-yl)methanol
for
(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 250B
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N-(15-chloro-6-P-hydroxy-2-(hydroxymethyl)-2-methylpropoxylpyridin-3-
yllsulfony1)-4-
(4-1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-l-y1)-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 250A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.05 (s, 1H), 9.22 (d,
1H), 8.51
(d, 1H), 8.42 (d, 1H), 8.09 (d, 1H), 7.66 (t, 2H), 7.43 - 7.46 (m, 2H), 7.04 -
7.09 (m, 2H), 6.75
(dd, 1H), 6.45 - 6.54 (m, 2H), 4.47 (s, 2H), 3.81 - 3.84 (m, 2H), 3.74 (d,
2H), 3.03 - 3.11 (m,
4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10 - 2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t,
2H), 1.16 (s, 3H),
0.94 (s, 6H).
EXAMPLE 251
4-(4-1112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(16-
R4-fluorotetrahydro-2H-pyran-4-y1)methoxylpyridin-3-yllsulfony1)-2-(1H-pyrrolo
112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 251A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting (4-fluorotetrahydro-2H-pyran-4-

yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-6-
chloropyridine-3-
sulfonamide for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 251B
6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
To a suspension of 5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-
yl)methoxy)pyridine-3-sulfonamide (200 mg) and cyclohexene (0.549 mL) in ethyl
acetate
(10 mL) was added 10% palladium on carbon (57.6 mg). The suspension was
stirred for 60
minutes at 120 C. The reaction mixture was filtered and concentrated. The
product was
purified by reverse-phase flash chromatography (C18, 150g, 10%-100%
acetonitrile/H20/trifluoroacetic acid 0.1%).
EXAMPLE 251C
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4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 6-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yl} sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 251B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.06 (s, 1H), 9.29 (d,
1H), 8.50
(dd, 1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.66 - 7.70 (m, 1H), 7.64 (d, 1H), 7.44
(d, 2H), 7.07 (d,
2H), 6.84 (d, 1H), 6.75 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.50 (d, 2H),
3.81 - 3.89 (m,
2H), 3.70 - 3.81 (m, 2H), 3.02 - 3.12 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H),
2.10 - 2.18 (m, 4H),
1.97 (s, 2H), 1.77 - 1.94 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 252
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { [4-
(1 114-(1,3-difluoropropan-2-yl)morpholin-2-yll methyl I amino)-3-nitrophenyll
sulfonyl I -2-
(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 252A
tert-butyl (4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate
The title compound was prepared by substituting 1,3-difluoropropan-2-one for
4'-
chlorobipheny1-2-carboxaldehyde and tert-butyl morpholin-2-ylmethylcarbamate
for tert-
butyl piperazine-l-carboxylate in EXAMPLE 1A.
EXAMPLE 252B
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methanamine
A solution of EXAMPLE 252A (538 mg) in dioxane (4 mL) was treated with 4.0M
HC1 in dioxane solution (1.8 mL). The reaction was stirred at room temperature
overnight.
The reaction mixture was concentrated under vacuum and used without further
purification.
EXAMPLE 252C
4-((4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 252B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 252D
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4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-114-
(114-(1,3-difluoropropan-2-y1)morpholin-2-yllmethyllamino)-3-
nitrophenyllsulfonyll-2-
(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 252C for EXAMPLE
1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.64 (s, 1H), 8.59 (t, 1H), 8.57 (d, 1H), 8.04 (d,
1H), 7.83 (dd, 1H),
7.51 (m, 3H), 7.33 (d, 2H), 7.07 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.39
(m, 1H), 6.19 (d,
1H), 4.69 (t, 2H), 4.57 (t, 2H), 3.85 (m, 1H), 3.70 (m, 1H), 3.52 (m, 2H),
3.41 (m, 2H), 3.07
(br s, 4H), 2.91 (d, 1H), 2.74 (m, 3H), 2.59 (m, 1H), 2.43 (m, 1H), 2.20 (m,
4H), 2.15 (m,
2H), 1.95 (br s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
EXAMPLE 253
N-1(5-chloro-6-111-(cyanomethyl)piperidin-4-yllmethoxylpyridin-3-yl)sulfonyll -
444-11244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 253A
tert-butyl 4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)piperidine-1-
carboxylate
The title compound was prepared by substituting tert-butyl 4-
(hydroxymethyl)piperidine-l-carboxylate for tetrahydro-2H-pyran-4-yl)methanol
and
EXAMPLE 40A for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 253B
5-chloro-6-(piperidin-4-ylmethoxy)pyridine-3-sulfonamide ditrifluoroacetic
acid
The title compound was prepared by substituting EXAMPLE 253A for EXAMPLE
39A in EXAMPLE 39B.
EXAMPLE 253C
5-chloro-6-((1-(cyanomethyl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide
EXAMPLE 253B (0.061 g), 2-chloroacetonitrile (0.017 g), sodium carbonate
(0.025
g) and N,N-dimethylformamide (1 mL) were combined in a 4-mL vial and heated at
60 C
overnight. The cooled reaction mixture was diluted with ethyl acetate, washed
with water
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and brine, dried (MgSO4), filtered and concentrated. The concentrate was
chromatographed
on silica gel with 2-10% methanol in CH2C12 as the eluent.
EXAMPLE 253D
N- [(5-chloro-6- { 111-(cyanomethyl)piperidin-4-yl[methoxy}pyridin-3-
yl)sulfonyl[-4-(4- { [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo 1L2,3 -
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 253C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400 MHz, pyridine-
d5) 8 13.04 (s, 1H), 9.14 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (t, 2H),
7.44 (m, 2H), 7.07
(m, 2H), 6.74 (dd, 1H), 6.50 (m, 2H), 4.18 (d, 2H), 3.64 (s, 2H), 3.05 (s,
4H), 2.77 (m, 4H),
2.24 (m, 4H), 2.13 (m, 4H), 1.97 (s, 2H), 1.69 (m, 3H), 1.41 (m, 4H), 0.93 (s,
6H).
EXAMPLE 254
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { (3R)-1-[2-(2-methoxyethoxy)ethyl[pyrrolidin-3-yllamino)-3-
nitrophenyl[sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 254A
(R)-tert-butyl 3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate
The title compound was prepared by substituting (R)-tert-butyl 3-
aminopyrrolidine-1-
carboxylate for 1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 254B
(R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesufonamide
The title compound was prepared by substituting EXAMPLE 254A for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 254C
(R)-4-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3-ylamino)-3-
nitrobenzenesufonamide
To a solution of (R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide (440
mg) in
N,N-dimethylformamide (10 mL) was added sodium carbonate (132 mg) and 1-bromo-
2-(2-
methoxyethoxy)ethane (0.155 mL). The reaction mixture was heated at 60 C for
18 hours
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and after an aqueous workup, the crude product was purified on silica gel with
a 2.5 - 10%
methanol in methylene chloride gradient to provide the title compound.
EXAMPLE 254D
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { (3R)-1-[2-(2-methoxyethoxy)ethyl[pyrrolidin-3-yllamino)-3-
nitrophenyl[sulfonyll-2-(1H-
pyrrolo[2,3-b[pyridin-5-yl-oxy)benzamide
The title compound was prepared by substituting EXAMPLE 254C for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d5) 8 12.96 (m, 1H), 9.25 (m,
1H),
8.57 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.66 (t, 1H) 7.64 (d,
1H), 7.44 (d, 2H),
7.07 (d, 2H), 6.82 (d, 1H), 6.76 (dd, 1H), 6.55 (m, 1H), 6.47 (m, 1H), 5.26
(br s, 1H), 4.02
(m, 1H), 3.63 (m, 4H), 3.53 (m, 2H), 3.28 (s, 3H), 3.07 (m, 4H), 2.89 - 2.81
(m, 2H), 2.78 (s,
2H), 2.75 - 2.66 (m, 3H), 2.37 (m, 1H), 2.26 (m, 2H), 2.24 - 2.18 (m, 1H),
2.15 (m, 4H), 1.97
(s, 2H), 1.65 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 255
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(4-
{ R3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl[aminol-3-nitrophenyl)sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 255A
(R)-4-(1-(2-(dimethylamino)acetyl)pyrrolidin-3-ylamino)-3-
nitrobenzenesufonamide
The title compound was prepared by substituting 2-(dimethylamino)acetyl
chloride,
hydrochloric acid for 1-bromo-2-(2-methoxyethoxy)ethane in EXAMPLE 254C except
the
reaction was stirred at ambient temperature for 18 hours.
EXAMPLE 255B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- [(4-
{ R3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl[aminol-3-nitrophenyl)sulfonyll-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 255A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine - d5) 8 13.01 (d, 1H), 9.26
(m, 1H),
8.46 - 8.33 (m, 3H), 8.14 (d, 1H), 7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H),
7.01 ¨ 6.89 (m,
1H), 6.76 (dd, 1H), 6.55 (m, 1H), 6.48 (m, 1H), 5.32 (br s, 1H), 4.27 - 4.14
(m, 1H), 4.05-
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3.95 (m, 1H), 3.82 - 3.62 (m, 3H), 3.27 - 3.15 (m, 2H), 3.07 (m, 4H), 2.77 (s,
2H), 2.34 (2,
3H), 2.32 (s, 3H), 2.30 - 2.20 (m, 3H), 2.15 (m, 4H), 1.97 (s, 2H), 1.87 -
1.81 (m, 1H), 1.39
(t, 2H), 0.94 (s, 6H).
EXAMPLE 256
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(3 -
nitro-4- { 111-(oxetan-3-yl)azetidin-3-yll amino } phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
EXAMPLE 256A
tert-butyl 3-(2-nitro-4-sulfamoylphenylamino)azetidine-1-carboxylate
The title compound was prepared by substituting tert-butyl 3-aminoazetidine-1-
carboxylate for 4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.
EXAMPLE 256B
4-(azetidin-3-ylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 256A for (S)-1-tert-
butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate in EXAMPLE 168A.
EXAMPLE 256C
3-nitro-4-(1-(oxetan-3-yl)azetidin-3-ylamino)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 256B for tert-butyl
piperazine-l-carboxylate and 3-oxetanone for 4'-chlorobipheny1-2-
carboxaldehyde in
EXAMPLE 1A.
EXAMPLE 256D
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- R3 -
nitro-4- { 111-(oxetan-3-yl)azetidin-3-yll amino } phenyl)sulfonyll -2-(1H-
pyrrolol2,3-blpyridin-
5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 256C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.04 (s, 1H), 9.27 (d,
1H), 8.62
(d, 1H), 8.42 (d, 1H), 8.35 (dd, 1H), 8.09 (d, 1H), 7.67 (m, 1H), 7.63 (d,
1H), 7.44 (m, 2H),
7.07 (m, 2H), 6.76 (dd, 1H), 6.67 (d, 1H), 6.55 (d, 1H), 6.48 (dd, 1H), 4.66
(t, 2H), 4.58 (m,
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2H), 4.23 (m, 1H), 3.71 (m, 3H), 3.12 (dd, 2H), 3.07 (m, 4H), 2.77 (s, 2H),
2.26 (t, 2H), 2.14
(t, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 257
N-1(5-chloro-6-111-(cyanomethyl)-4-fluoropiperidin-4-yllmethoxylpyridin-3-
yl)sulfonyll -4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 257A
tert-butyl 4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-
1-carboxylate
The title compound was prepared by substituting EXAMPLE 126A for (tetrahydro-
2H-pyran-4-yl)methanol and EXAMPLE 40A for 4-fluoro-3-nitrobenzenesulfonamide
in
EXAMPLE 24A.
EXAMPLE 257B
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide
ditrifluoroacetic acid
The title compound was prepared by substituting EXAMPLE 257A for EXAMPLE
39A in EXAMPLE 39B.
EXAMPLE 257C
5-chloro-6-((1-(cyanomethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-
sulfonamide
EXAMPLE 257B (0.166 g) in acetonitrile (3 mL) was treated with 2-
chloroacetonitrile (0.027 g) and sodium carbonate (0.064 g), heated at 60 C
overnight, cooled
to room temperature and chromatographed on silica gel with 0 to 3% methanol in
CH2C12 as
the eluent. The obtained solid was slurried in water, filtered, rinsed with
water and diethyl
ether, and dried in a vacuum oven at 80 C.
EXAMPLE 257D
N-1(5-chloro-6-111-(cyanomethyl)-4-fluoropiperidin-4-yllmethoxylpyridin-3-
yl)sulfonyll -4-
(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-
2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 257C for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400 MHz, pyridine-
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d5) 8 13.05 (s, 1H), 9.12 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H),
7.66 (m, 2H), 7.44
(m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.50 (m, 2H), 4.49 (d, 2H), 3.72 (s,
2H), 3.06 (m, 4H),
2.77 (s, 2H), 2.73 (m, 4H), 2.26 (t, 2H), 2.13 (m, 4H), 2.07 (m, 2H), 1.90 (m,
4H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 258
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- { [4-
( { R2R)-4-(N,N-dimethylglycyl)morpholin-2-yllmethyllamino)-3-nitrophenyll
sulfony11-2-
(1H-pyrrolo[2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 258A
(S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1
g) in
dichloromethane (50 mL) was added triethylamine (1.604 mL) and 4-methylbenzene-
1-
sulfonyl chloride (1.097 g). The mixture was stirred at ambient temperature
under nitrogen
for 72 hours. The reaction was diluted with methylene chloride (50 mL) and
brine (100 mL).
The brine layer was extracted with methylene chloride (75 mL). The combined
organics
were dried over sodium sulfate, filtered and concentrated. The crude material
was purified on
a silica gel column eluting with a 15-65 % ethyl acetate in hexane gradient to
provide the title
compound.
EXAMPLE 258B
(S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate
A solution of EXAMPLE 258A (1.66 g) and sodium azide (0.581 g) in anhydrous
N,N-dimethylformamide (10 mL) was stirred at 90 C for 4 hours. The mixture
was cooled
and concentrated to dryness. The residue was taken up in 5% aqueous sodium
carbonate
solution and extracted with methylene chloride. The organic solution was dried
(MgSO4),
filtered and concentrated to give a solid.
EXAMPLE 258C
(R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate
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This compound was obtained by hydrogenation of EXAMPLE 258B under 60 psi of
hydrogen over 10% palladium on carbon in methanol for 24 hours, followed by
filtration and
evaporation of the solvent.
EXAMPLE 258D
(R)-tert-butyl 2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-
carboxylate
The title compound was prepared by substituting EXAMPLE 258C for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 258E
(S)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 258D for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 258F
(R)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-
nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 258E for EXAMPLE
134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyl iodide in
EXAMPLE
134B.
EXAMPLE 258G
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { [(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl[methyllamino)-3-
nitrophenyl[sulfonyll-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 258F for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.27 (d,
1H),
8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (dd, 1H), 6.75 (d, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H),
4.20 (dd, 1H),
3.95-3.76 (m, 2H),3.60-3.40 (m, 3H),3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m,
4H), 2.80
(m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94
(s, 6H).
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EXAMPLE 259
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { [(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl[methyllamino)-3-
nitrophenyl[sulfonyll-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 259A
(R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate
The title compound was prepared by substituting (R)-tert-butyl 2-
(hydroxymethyl)morpholine-4-carboxylate for (S)-tert-butyl 2-
(hydroxymethyl)morpholine-
4-carboxylate in EXAMPLE 258A.
EXAMPLE 259B
(R)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate
The title compound was prepared by substituting EXAMPLE 259A for EXAMPLE
258A in EXAMPLE 258B.
EXAMPLE 259C
(S)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate
The title compound was prepared by substituting EXAMPLE 259B for EXAMPLE
258B in EXAMPLE 258C.
EXAMPLE 259D
(S)-tert-butyl 2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-
carboxylate
The title compound was prepared by substituting EXAMPLE 259C for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
EXAMPLE 259E
(R)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 259D for EXAMPLE
113A in EXAMPLE 134A.
EXAMPLE 259F
(S)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-
nitrobenzenesulfonamide
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The title compound was prepared by substituting EXAMPLE 259E for EXAMPLE
134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyl iodide in
EXAMPLE
134B.
EXAMPLE 259G
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N- { [4-
( { [(2S)-4-(N,N-dimethylglycyl)morpholin-2-yllmethyllamino)-3-nitrophenyll
sulfony11-2-
(1H-pyrrolo[2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 259F for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (500MHz, pyridine-d5) 8 13.00 (s, 1H), 9.27 (d,
1H),
8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d,
2H), 6.94 (dd, 1H), 6.75 (d, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H),
4.20 (dd, 1H),
3.95-3.76 (m, 2H),3.60-3.40 (m, 3H),3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m,
4H), 2.80
(m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94
(s, 6H).
EXAMPLE 260
N- [(5-chloro-6- { [1-(N,N-dimethylglycyl)piperidin-4-yll methoxy}pyridin-3-
yl)sulfonyll -4-
(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-2-(1H-
pyrrolo[2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 260A
5-chloro-6-((1-(2-(dimethylamino)acetyl)piperidin-4-yl)methoxy)pyridine-3-
sulfonamide
EXAMPLE 253B (0.061 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid
(0.061 g), and sodium carbonate (0.032 g) were combined in a 4-mL vial with
N,N-
dimethylformamide (2 mL). The mixture was stirred at ambient temperature for 3
days.
Additional 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.037 g),
sodium carbonate
(0.032 g) and N,N-dimethylformamide (1 mL) were added and stilling was
continued for 24
hours. The reaction mixture was diluted with ethyl acetate, washed with water
and brine,
dried (MgSO4), filtered, concentrated and chromatographed on silica gel with 0
to 20%
methanol in CH2C12 as the eluent.
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EXAMPLE 260B
N-R5-chloro-6- { 111-(N,N-dimethylglycyl)piperidin-4-yllmethoxy}pyridin-3-
yl)sulfonyll -4-
(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl}piperazin-l-
y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 260A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, pyridine-d5) 8 12.91 (s, 1H), 9.16 (d,
1H), 8.75
(d, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.45 (m, 2H),
7.09 (m, 2H),
6.77 (dd, 1H), 6.60 (d, 1H), 6.45 (d, 1H), 4.81 (d, 1H), 4.15 (m, 3H), 3.24
(m, 2H), 3.04 (m,
4H), 2.89 (m, 1H), 2.79 (s, 2H), 2.53 (m, 1H), 2.29 (m, 6H), 2.26 (m, 2H),
2.18 (m, 4H), 1.98
(m, 2H), 1.91 (m, 1H), 1.71 (m, 2H), 1.39 (t, 2H), 1.25 (m, 2H), 0.94 (s, 6H).
EXAMPLE 261
N- 11(5 -chloro-6- { R3R)-1-(2,2-difluoroethyl)pyrrolidin-3-ylloxylpyridin-3-
yl)sulfonyll -4-(4-
{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 261A
(R)-tert-Butyl 3-(3-chloro-5-sulfamoylpyridin-2-yloxy)pyrrolidine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide and (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate
for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 261B
(R)-5-Chloro-6-(pyrrolidin-3-yloxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 261A for tert-butyl (4-

(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in EXAMPLE 252B.
EXAMPLE 261C
(R)-5-chloro-6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)pyridine-3-sulfonamide
A mixture of EXAMPLE 261B (353 mg), 1, 1-difluoro-2-iodoethane (268 mg),
sodium carbonate (283 mg) in N,N-dimethylformamide (10mL) was heated at 80 C
overnight. The reaction mixture was cooled to room temperature and diluted
with ethyl
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acetate. The organic phase was washed with water, brine, dried over magnesium
sulfate,
filtered, and concentrated. The residue was loaded onto silica gel column and
eluted using a
gradient of 0.5 to 3 % methanol in dichloromethane to provide the title
compound.
EXAMPLE 261D
N- R5 -chloro-6- { R3R)-1-(2,2-difluoroethyl)pyrrolidin-3-ylloxy I pyridin-3 -
yl)sulfony11-4-(4-
{ 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-l-y1)-
2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 261C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.55 (s, 1 H),
8.04 (s,
1 H), 7.95 (d, 1 H), 7.58 (d, 1 H), 7.44 (t, 1 H), 7.35 (m, 3 H), 7.05 (d, 2
H), 6.64 (dd, 1 H),
6.33 (m, 1 H), 6.24 (d, 1 H), 6.25-5.97 (m, 1 H), 5.39 (m, 1 H), 2.98 (m, 6
H), 2.86 (m, 6 H),
2.55 (m, 2 H), 2.24 (m, 7 H), 1.96 (s, 2 H), 1.83 (m, 1 H), 1.39 (t, 2 H),
0.93 (s, 6 H)
EXAMPLE 262
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- [O-
f R3R)-1-(cyanomethyl)pyrrolidin-3-yll amino I -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 262A
(R)-4-(1-(cyanomethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesufonamide
The title compound was prepared by substituting 2-bromoacetonitrile for 1-
bromo-2-
(2-methoxyethoxy)ethane in EXAMPLE 254C.
EXAMPLE 262B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-N- 11(4-
{ R3R)-1-(cyanomethyl)pyrrolidin-3-yll amino I -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 262A for EXAMPLE
130C in EXAMPLE 130D. 1H NMR (400 MHz, pyridine - d5) 8 13.03 (s, 1H), 9.27
(d, 1H),
8.53 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H), 7.67 - 7.64 (m, 2H),
7.44 (d, 2H), 7.07
(d, 2H), 6.81 (d, 1H), 6.76 (dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 5.15 (br s,
1H), 4.10 (m,
1H), 3.89 (s, 2H), 3.07 (m, 4H), 2.93 - 2.86 (m, 2H), 2.80 - 2.77 (m, 3H),
2.61 - 2.53 (m, 1H),
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2.31 - 2.21 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.75 - 1.68 (m, 1H), 1.39 (t,
2H), 0.94 (m,
6H).
EXAMPLE 263
4-14-1(4'-chlorobipheny1-2-yl)methyll -4-methoxypiperidin-l-yll-N-(15-chloro-6-
1(4-
fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 263A
tert-butyl 1-oxa-6-azaspiro12.51octane-6-carboxylate
Sodium hydride (6.63 g, 60% in mineral oil) was added to trimethylsulfoxonium
iodide (36.5 g) in dimethyl sulfoxide (150 mL) and tetrahydrofuran (150 mL),
was and stirred
for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (25.4 g) was added
and the reaction
was stirred for 3 hours. The reaction was poured into water (800 mL) and
extracted three
times with ether. The combined extracts were washed three times with water,
and brine, dried
over Na2SO4, filtered, and concentrated to yield the crude product which was
used without
further purification.
EXAMPLE 263B
tert-butyl 4-(2-(benzyloxy)benzy1)-4-hydroxypiperidine-1-carboxylate
(2-(Benzyloxy)phenyl)magnesium bromide (33.8 mL, 1M) was added to a solution
of
EXAMPLE 263A (6.0 g) and CuI (1.07 g) in tetrahydrofuran (220 mL) at 0 C over
10
minutes. The reaction was quenched with pH 7 buffer (20 mL), extracted twice
with ether,
and the combined extracts were washed with brine, dried over Na2SO4, filtered,
and
concentrated. The crude product was chromatographed on silica gel using 2-20%
ethyl
acetate in hexanes to provide the title compound.
EXAMPLE 263C
tert-butyl 4-hydroxy-4-(2-hydroxybenzyl)piperidine-1-carboxylate
EXAMPLE 263B (11.5 g) and methanol (120 mL) were added to Raney Nickel
(1.150 g) in a 250 mL SS pressure bottle and stirred for 1 hour at 30 psi
under hydrogen. The
mixture was filtered through a nylon membrane and the solution was
concentrated to yield
the title compound.
EXAMPLE 263D
tert-butyl 4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-
carboxylate
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A mixture of EXAMPLE 263C (4.6 g), N-phenylbis(trifluoromethanesulfonimide)
(5.88 g), and Hunig's base (2.88 mL) in dichloromethane (100 mL) was stirred
for 24 hours.
The mixture was concentrated and chromatographed on silica gel using 5-50%
ethyl acetate
in hexanes to provide the title compound.
EXAMPLE 263E
tert-butyl 4((4'-chlorobipheny1-2-y0methyl)-4-hydroxypiperidine-1-carboxylate
A mixture of EXAMPLE 263D (4.3 g), 4-chlorophenylboronic acid (1.84 g), K3PO4
(2.91 g), and 11,1'-bis(diphenylphosphino)ferroceneldichloropalladium(II)
(0.36 g) in 2-
methyltetrahydrofuran (50 mL) was stirred at 70 C for 24 hours. The reaction
was cooled and
quenched with water (50 mL), extracted twice with ether, and the combined
extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated. The crude
product was
chromatographed on silica gel using 5-30% ethyl acetate in hexanes to provide
the title
compound.
EXAMPLE 263F
tert-butyl 4((4'-chlorobipheny1-2-yl)methyl)-4-methoxypiperidine-1-carboxylate

Sodium hydride (0.36 g, 60% in mineral oil) was added to EXAMPLE 263E (4.3 g),

in tetrahydrofuran (40 mL) and the reaction was stirred for 10 minutes.
Hexamethylphosphoramide (5 mL) and CH3I (2.34 mL) were added and the reaction
was
stirred at 50 C for 18 hours. The reaction was cooled and quenched with water
(50 mL),
extracted twice with ether, and the combined extracts were washed with brine,
dried over
Na2SO4, filtered, and concentrated. The crude product was chromatographed on
silica gel
using 5-25% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 263G
4((4'-chlorobipheny1-2-y0methyl)-4-methoxypiperidine
The title compound was prepared by substituting EXAMPLE 263F for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 263H
methyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(4'-chlorobipheny1-2-
y0methyl)-4-
methoxypiperidin-1-yl)benzoate
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A solution of EXAMPLE 263G (1.4 g), EXAMPLE 3H (1.06 g) and Hunig's base
(0.75 mL) in dimethylsulfoxide (20 mL) was stirred at 120 C for 18 hours. The
reaction was
cooled and quenched with water (200 mL), extracted three times with ether, and
the
combined extracts were washed three times with water, and brine, dried over
Na2SO4,
filtered, and concentrated. The crude product was chromatographed on silica
gel using 5-50%
ethyl acetate in hexanes to provide the title compound.
EXAMPLE 2631
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-((4'-chlorobipheny1-2-yl)methyl)-4-
methoxypiperidin-l-yl)benzoic acid
The title compound was prepared by substituting EXAMPLE 263H for EXAMPLE 31
in EXAMPLE 3J.
EXAMPLE 263J
4-14- [(4'-chlorobipheny1-2-yl)methyll -4-methoxypiperidin-1-yll-N-(15-chloro-
6- 11(4-
fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yllsulfony1)-2-(1H-pyrrolo
[2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 2631 for EXAMPLE 1E
and EXAMPLE 96A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.71 (s, 1H), 11.58 (br s, 1H), 8.58 (d, 1H), 8.28
(d, 1H), 8.05 (d,
1H), 7.56 (d, 1H), 7.52 (m, 1H), 7.46 (d, 1H), 7.44 (d, 2H), 7.28 (m, 5H),
7.11 (dd, 1H), 6.62
(dd, 1H), 6.41 (dd, 1H), 6.11 (d, 1H), 4.54 (d, 2H), 3.75 (m, 2H), 3.59 (m,
2H), 3.20 (m, 2H),
2.97 (s, 3H), 2.81 (m, 2H), 2.74 (m, 2H), 1.89 (m, 2H), 1.83 (m, 2H), 1.36 (m,
2H), 1.09 (m,
2H).
EXAMPLE 264
4-14- R4'-chlorobipheny1-2-yl)methyll -4-methoxyp iperidin-1 -yll-N-(13 -nitro-
4- Rtetrahydro-
2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-pyrrolo1L2,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 2631 for EXAMPLE 1E
in EXAMPLE 1G. 1H NMR (300MHz, dimethylsulfoxide-d6) 8 11.71 (s, 1H), 11.40
(br s,
1H), 8.62 (t, 1H), 8.58 (d, 1H), 8.03 (d, 1H), 7.81 (dd, 1H), 7.54 (m, 2H),
7.44 (m, 3H), 7.28
(m, 5H), 7.13 (dd, 1H), 6.62 (dd, 1H), 6.41 (dd, 1H), 6.11 (d, 1H), 3.85 (dd,
2H), 3.31 (m,
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4H), 3.20 (m, 2H), 2.97 (s, 3H), 2.81 (m, 2H), 2.73 (m, 2H), 1.89 (m, 1H),
1.62 (m, 2H), 1.38
(m, 2H), 1.25 (m, 2H), 1.09 (m, 2H).
EXAMPLE 265
4-(4-119-(4-chloropheny0-3-(1,3-difluoropropan-2-y0-3-azaspiro15.51undec-8-en-
8-
yllmethyllpiperazin-1-y1)-N-(13-nitro-4-1(tetrahydro-2H-pyran-4-
ylmethyl)aminolphenyllsulfony0-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 265A
benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate
To a solution of benzyl 4-formylpiperidine-1-carboxylate (12.5g) in toluene
(120 mL)
was added piperidine (6.46g). The mixture was stirred at reflux under a Dean-
Stark trap
overnight. The mixture was then concentrated under vacuum and the residue was
used
directly in the next step.
EXAMPLE 265B
benzyl 9-oxo-3-azaspiro15.51undec-7-ene-3-carboxylate
To a solution of EXAMPLE 265A (15.88g) in ethanol (300 mL) was added but-3-
enone (3.89 g). The mixture was stirred at reflux overnight. Then acetic acid
(30 mL) was
added to the mixture which was stirred at reflux again overnight. The mixture
was then
concentrated under vacuum and the residue was diluted with ethyl acetate (400
mL) and
washed with water and brine and dried over Na2SO4. After filtration and
evaporation of the
solvent, column purification gave the title compound.
EXAMPLE 265C
benzyl 9-hydroxy-3-azaspiro15.51undecane-3-carboxylate
EXAMPLE 265B (21 g) and tetrahydrofuran (160 mL) were added to 5% Pt-C wet
(3.15 g) in a 250 mL pressure bottle and stirred for 1 hour at 30 psi and room
temperature.
The mixture was filtered though a nylon membrane and the filtrate was
concentrated under
vacuum to provide the title compound.
EXAMPLE 265D
benzyl 9-oxo-3-azaspiro15.51undecane-3-carboxylate
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To a solution of EXAMPLE 265C (8.0 g) in dichloromethane (200 mL) was added
Dess-Martin Periodinane (11.2 g). The mixture was stirred overnight. The
mixture was
diluted with ethyl acetate (400 mL) and washed with 2N aqueous NaOH, water,
and brine.
After drying over Na2SO4 and filtration, concentration of the solvent gave the
crude product
which was used directly in the next reaction without further purification.
EXAMPLE 265E
benzyl 9-chloro-8-formy1-3-azaspiro15.51undec-8-ene-3-carboxylate
Phosphorus oxychloride (2.33 mL) was added dropwise to a cooled (0 C) solution
of
EXAMPLE 265D (7.5 g) in N,N-dimethylformamide (10 mL) and dichloromethane (30
mL).
The mixture was then stirred overnight before it was diluted with ethyl
acetate (300 mL) and
washed with aqueous sodium acetate, water (3x), and brine and dried over
Na2SO4. After
filtration and concentration, the crude product was used directly in the next
reaction without
further purification.
EXAMPLE 265F
benzyl 9-(4-chloropheny1)-8-formy1-3-azaspiro15.51undec-8-ene-3-carboxylate
To a mixture of 4-chlorophenylboronic acid (5.94 g), EXAMPLE 265E (11.01 g),
palladium(II) acetate (142 mg), K2CO3 (13.2 g) and tetrabutylammonium bromide
(10.2 g)
was added water (120 mL). The mixture was stirred at 50 C overnight. The
mixture was
diluted with ethyl acetate (400 mL) and washed with water (3x) and brine and
dried over
Na2SO4. After filtration and concentration, the residue was loaded on a column
and eluted
with 5 to 20% ethyl acetate in hexane to provide the title compound.
EXAMPLE 265G
benzyl 8-((4-(3-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-
(methoxycarbonyl)phenyl)piperazin-1-
yl)methyl)-9-(4-chloropheny1)-3-azaspiro15.51undec-8-ene-3-carboxylate
To a solution of EXAMPLE 15F (1.37 g) and EXAMPLE 265F (1.65 g) in
dichloromethane (20 mL) was added sodium triacetoxyborohydride (1.24 g). The
mixture
was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and
washed with
2N aqueous NaOH, water and brine. After drying over Na2504, the mixture was
filtered and
the solvent was evaporated under vacuum to provide the title compound.
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EXAMPLE 265H
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(9-(4-chloropheny1)-3-
azaspirol5.51undec-8-en-8-y1)methyl)piperazin-1-y1)benzoate
EXAMPLE 265G (2 g) and tetrahydrofuran (10 mL) were added to 20% Pd(OH)2-C,
wet (0.400 g) in a 50 mL pressure bottle and stirred for 16 hours at 30 psi
and room
temperature. The mixture was filtered though a nylon membrane and evaporation
of the
solvent gave the title compound.
EXAMPLE 2651
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(9-(4-chloropheny1)-3-(1,3-
difluoropropan-2-y1)-3-azaspirol5.51undec-8-en-8-y1)methyl)piperazin-1-
y1)benzoate
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added 1,
3-difluoroacetone (139 mg) and sodium triacetoxyborohydride (157 mg). The
mixture was
stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and
washed with 2N
aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was
filtered and the
solvent was evaporated under vacuum to provide the title compound.
EXAMPLE 265J
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(9-(4-chloropheny1)-3-(1,3-
difluoropropan-2-y1)-
3-azaspirol5.51undec-8-en-8-yl)methyl)piperazin-1-y1)benzoic acid
To a solution of EXAMPLE 2651 (320 mg) in tetrahydrofuran (4 mL) and methanol
(2 mL) was added LiOH H20 (120 mg) and the solution was stirred overnight. The
reaction
was cooled, carefully neutralized with 1N aqueous HC1 and extracted with
dichloromethane
(3x 50 mL). The combined organic layers were washed with brine (25 mL), dried
over
sodium sulfate, filtered and concentrated under vacuum to provide the title
compound.
EXAMPLE 265K
4-(4- { [9-(4-chloropheny1)-3-(1,3-difluoropropan-2-y1)-3-azaspirol5.51undec-8-
en-8-
yllmethyl I piperazin-l-y1)-N-( { 3-nitro-4- Rtetrahydro-2H-pyran-4-
ylmethyl)aminolphenyl } sulfony1)-2-(1H-pyrrolo [2,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 265J for EXAMPLE 1E
in EXAMPLE 1G. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.61 (s, 1 H), 8.49
(d, 2
H), 7.72 (m, 1 H), 7.49 (m, 2 H), 7.32 (d, 2 H), 7.07 (m, 3 H), 6.65 (dd, 1
H), 6.35 (d, 1 H),
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6.20 (m, 1 H), 4.66 (m, 2 H), 4.50 (m, 2 H), 3.84 (m, 2 H), 3.04 (m, 5 H),
2.70 (m, 6 H), 2.23
(m, 6 H), 2.00 (m, 4 H), 1.35 (m, 12 H).
EXAMPLE 266
4-(4-{ 1L9-(4-chloropheny1)-3-isopropyl-3 -azaspiro [5.51undec-8-en-8-yll
methyl}piperazin-1-
y1)-N-(13 -nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 266A
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(9-(4-chloropheny1)-3-
isopropy1-3-
azaspirol5.51undec-8-en-8-y1)methyl)piperazin-1-y1)benzoate
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added
acetone (143 mg) and sodium triacetoxyborohydride (157 mg). The mixture was
stirred
overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with
2N aqueous
NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and
the solvent
was evaporated under vacuum to provide the title compound.
EXAMPLE 266B
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-49-(4-chloropheny1)-3-isopropy1-3-
azaspirol5.51undec-8-en-8-yl)methyl)piperazin-l-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 266A for EXAMPLE
2651 in EXAMPLE 265J.
EXAMPLE 266C
4-(4-{ [9-(4-chloropheny1)-3-isopropyl-3 -azaspiro [5.51undec-8-en-8-yll
methyl}piperazin-1-
y1)-N-(13 -nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-
(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE
1E in EXAMPLE 1G. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 11.54 (s, 1 H),
8.38 (m,
2 H), 7.93 (d, 1 H), 7.60 (m, 3 H), 7.39 (m, 4 H), 7.09 (d, 2 H), 6.85 (d, 1
H), 6.63 (dd, 1 H),
6.27 (dd, 2 H), 3.84 (m, 3 H), 3.08 (m, 8 H), 2.71 (s, 3 H), 2.15 (m, 8 H),
1.71 (m, 9 H), 1.24
(m, 11 H)
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EXAMPLE 267
4-(4-{ [9-(4-chloropheny1)-3-(1,3-difluoropropan-2-y1)-3-azaspiro[5.51undec-8-
en-8-
yflmethyllpiperazin-1-y1)-N-{ [5-chloro-6-(tetrahydro-2H-pyran-4-
ylmethoxy)pyridin-3-
yllsulfonyl } -2-(1H-pyrrolo [2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 265J for EXAMPLE 1E
and EXAMPLE 40B for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.56 (s, 1 H), 8.38 (s, 1 H), 8.06 (m, 1 H), 7.57 (d,
1 H), 7.38 (m, 5
H), 7.07 (m, 3 H), 6.64 (dd, 1 H), 6.33 (d, 1 H), 6.23 (m, 1 H), 4.68 (d, 2
H), 4.52 (d, 2 H),
4.21 (d, 2 H), 3.86 (dd, 2 H), 3.08 (m, 8 H), 2.71 (m, 6 H), 2.10 (m, 12 H),
1.42 (m, 7 H).
EXAMPLE 268
4-(4- { [9-(4-chloropheny1)-3-isopropyl-3 -azaspiro [5.51undec-8-en-8-yll
methyl } piperazin-1-
y1)-N- { [5 -chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-y11 sulfonyl
} -2-(1H-
pyrrolo[2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE
1E and EXAMPLE 40B for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.49 (s, 1 H), 8.28 (d, 1 H), 7.94 (dd, 2 H), 7.60
(d, 1 H), 7.35 (m, 4
H), 7.08 (m, 2 H), 6.61 (dd, 1 H), 6.28 (dd, 2 H), 4.18 (d, 2 H), 3.85 (m, 2
H), 3.05 (m, 7 H),
2.71 (s, 3 H), 2.25 (m, 6 H), 2.02 (m, 2 H), 1.63 (m, 8 H), 1.30 (m, 9 H).
EXAMPLE 269
N-( { 5-chloro-6- [(4-fluoro-1-methylpiperidin-4-yl)methoxylpyridin-3-yl}
sulfony1)-4-(4- { [2-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yflmethyl}piperazin-1-y1)-2-(1H-
pyrrolo[2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 269A
5-chloro-6-((4-fluoro-1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamide
EXAMPLE 257B (0.131 g) in N,N-dimethylformamide (3.0 mL) was treated with
iodomethane (0.043 g) and sodium carbonate (0.079 g) and stirred at ambient
temperature for
3 days. The N,N-dimethylformamide was removed on high vacuum and the
concentrate was
chromatographed on amine functionalized silica gel with 0 to 2% methanol in
CH2C12 as the
eluent.
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EXAMPLE 269B
N-(15 -chloro-6- [(4-fluoro-1-methylpiperidin-4-yl)methoxy[pyridin-3-
yllsulfony1)-4-(4-1[2-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyllpiperazin-1-y1)-2-(1H-
pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 269A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, pyridine-d5) 8 13.01 (s, 1H), 9.11 (d,
1H), 8.71
(d, 1H), 8.44 (d, 1H), 8.16 (d, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H),
6.76 (dd, 1H),
6.54 (d, 1H), 6.49 (dd, 1H), 4.49 (d, 2H), 3.06 (m, 4H), 2.77 (s, 2H), 2.68
(m, 2H), 2.38 (m,
2H), 2.26 (m, 5H), 2.14 (t, 4H), 1.97 (m, 6H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 270
N-[(5-chloro-6-1[1-(N,N-dimethylglycy1)-4-fluoropiperidin-4-yflmethoxylpyridin-
3-
yflsulfonyfl -444-1 [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyllpiperazin-1-
y1)-2-(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 270A
5-chloro-6-((1-(2-(dimethylamino)acety1)-4-fluoropiperidin-4-
yl)methoxy)pyridine-3-
sulfonamide
EXAMPLE 257B (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid
(0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with
N,N-
dimethylformamide (3.0 mL) and stirred overnight at ambient temperature.
Additional
sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl
chloride,
hydrochloric acid (0.139 g) and stirring was continued over a second night.
The reaction
mixture was concentrated under high vacuum, slurried in CH2C12, filtered,
concentrated and
chromatographed on amine functionalized silica gel with 0 to 4% methanol in
CH2C12 as the
eluent.
EXAMPLE 270B
N- [(5-chloro-6-1 [1-(N,N-dimethylglycy1)-4-fluoropiperidin-4-yfl
methoxylpyridin-3 -
yl)sulfonyl] -444-1 [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yl[methyllpiperazin-1-
y1)-2-(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 270A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (500 MHz, pyridine-d5) 8 13.04 (s, 1H), 9.12 (d,
1H), 8.73
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(d, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H),
6.76 (dd, 1H),
6.52 (d, 1H), 6.49 (dd, 1H), 4.66 (d, 1H), 4.52 (dd, 2H), 4.07 (d, 1H), 3.46
(m, 1H), 3.40 (m,
1H), 3.30 (m, 1H), 3.11 (m, 1H), 3.06 (m, 4H), 2.77 (s, 2H), 2.35 (s, 6H),
2.26 (t, 2H), 2.14
(m, 4H), 2.05 (m, 2H), 1.97 (s, 2H), 1.81 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 271
4- { 4- R4'-chlorobipheny1-2-yl)methyll -4-fluoropiperidin-l-y1 } -N-( {3-
nitro-4- Rtetrahydro-
2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5-
yloxy)benzamide
EXAMPLE 271A
tert-butyl 4((4'-chlorobipheny1-2-y0methyl)-4-fluoropiperidine-1-carboxylate
A solution of EXAMPLE 263E (2.0 g) and diethylaminosulfur trifluoride (1.39
mL)
in dichloromethane (40 mL) was stirred for 24 hours. The reaction was quenched
with water
(30 mL), extracted twice with ether, and the combined extracts were washed
with water, and
brine, dried over Na2SO4, filtered, and concentrated. The crude product was
chromatographed
on silica gel using 5% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 271B
4((4'-chlorobipheny1-2-y0methyl)-4-fluoropiperidine
The title compound was prepared by substituting EXAMPLE 271A for EXAMPLE
1A in EXAMPLE 1B.
EXAMPLE 271C
methyl 2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(4'-chlorobipheny1-2-
y0methyl)-4-
fluoropiperidin-l-yl)benzoate
The title compound was prepared by substituting EXAMPLE 271B for EXAMPLE
263G in EXAMPLE 263H.
EXAMPLE 271D
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(4'-chlorobipheny1-2-y0methyl)-4-
fluoropiperidin-1-yl)benzoic acid
The title compound was prepared by substituting EXAMPLE 271C for EXAMPLE 31
in EXAMPLE 3J.
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EXAMPLE 271E
4- 14-1(4'-chlorobipheny1-2-yl)methyll-4-fluoropiperidin-l-yll-N-(13-nitro-4-
1(tetrahydro-
2H-pyran-4-ylmethyBaminolphenyllsulfony1)-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE
1E EXAMPLE 1G. 1H NMR (300MHz, dimethylsulfoxide-d6) 8 11.66 (s, 1H), 11.46
(br s,
1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.03 (d, 1H), 7.81 (dd, 1H), 7.52 (m, 3H),
7.44 (d, 2H), 7.28
(m, 5H), 7.14 (m, 1H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.19 (d, 1H), 3.84 (dd,
2H), 3.31 (m,
9H), 2.95 (d, 2H), 2.81 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.45 (m, 2H),
1.29 (m, 2H).
EXAMPLE 272
4- 14-1(4'-chlorobipheny1-2-yl)methy11-4-fluoropiperidin-1-yll-N-(15-chloro-6-
1(4-
fluorotetrahydro-2H-pyran-4-yl)methoxylpyridin-3-yllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE
1E and EXAMPLE 96A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.68 (s, 1H), 11.64 (br s, 1H), 8.58 (m, 1H), 8.25
(m, 1H), 8.03 (d,
1H), 7.70 (dd, 1H), 7.50 (m, 4H), 7.43 (m, 3H), 7.28 (m, 4H), 7.15 (m, 1H),
6.68 (dd, 1H),
6.40 (dd, 1H), 6.19 (d, 1H), 4.54 (d, 2H), 4.04 (m, 1H), 3.75 (m, 2H), 3.58
(m, 2H), 2.95 (d,
2H), 2.80 (m, 2H), 1.88 (m, 2H), 1.82 (m, 2H), 1.48 (m, 2H), 1.28 (m, 2H),
0.85 (m, 2H).
EXAMPLE 273
4-(4-119-(4-chloropheny1)-3-isopropy1-3-azaspiro15.51undec-8-en-8-
yllmethyllpiperazin-1-
y1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-N-(1 4- Rtetrahydro-2H-pyran-4-
ylmethyBaminol-3-
(trifluoromethyl)phenyllsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE
1E and EXAMPLE 42A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.57 (s, 1 H), 7.97 (d, 1 H), 7.77 (s, 1 H), 7.55 (m,
2 H), 7.45 (m, 1
H), 7.36 (m, 3 H), 7.08 (d, 2 H), 6.62 (dd, 2 H), 6.35 (dd, 1 H), 6.21 (d, 1
H), 3.82 (m, 3 H),
3.06 (m, 9 H), 2.72 (m, 3 H), 2.25 (m, 8 H), 2.09 (m, 2 H), 1.56 (m, 9 H),
1.20 (m, 10 H).
EXAMPLE 274
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N-R5-chloro-6- { R3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylloxy I pyridin-
3 -
yl)sulfonyll -4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll
methyl } piperazin-l-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 274A
(R)-5-chloro-6-(1-(3-fluoro-2-(fluoromethyl)propyl)pyrrolidin-3-yloxy)pyridine-
3-
sulfonamide
The title compound was prepared by substituting 1,3-difluoropropan-2-one for
4'-
chlorobipheny1-2-carboxaldehyde and EXAMPLE 261B for tert-butyl piperazine-1-
carboxylate in EXAMPLE 1A.
EXAMPLE 274B
N-R5-chloro-6- { R3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylloxy I pyridin-
3 -
yl)sulfonyll -4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll
methyl } piperazin-1 -
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 274A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.52 (s, 1 H),
8.32 (d,
1 H), 8.01 (d, 1 H), 7.93 (d, 1 H), 7.59 (d, 1 H), 7.42 (m, 1 H), 7.33 (m, 3
H), 7.05 (d, 2 H),
6.63 (dd, 1 H), 6.31 (dd, 1 H), 6.25 (d, 1 H), 5.38 (m, 1 H), 4.65 (t, 2 H),
4.53 (t, 2 H), 3.02
(s, 4 H), 2.94 (m, 5 H), 2.75 (s, 2 H), 2.66 (m, 1 H), 2.23 (m, 7 H), 1.96 (s,
2 H), 1.82 (m, 1
H), 1.39 (t, 2 H), 0.93 (s, 6 H).
EXAMPLE 275
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
nitro-4- [2- (tetrahydrofuran-3 -yloxy)ethoxylphenyl } sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 275A
3-(2-(benzyloxy)ethoxy)tetrahydrofuran
Tetrahydrofuran-3-ol (0.881 g) in tetrahydrofuran (15 mL) was treated with 60%
sodium hydride (0.8 g). After 10 minutes, ((2-bromoethoxy)methyl)benzene (3.23
g) was
added. The solution was stirred for 16 hours. The reaction mixture was
partitioned between
water and ethyl acetate. The aqueous layer was separated, and was extracted
with additional
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ethyl acetate twice. The combined organic layers were washed with brine, dried
over MgSO4,
filtered, and concentrated. The residue was purified by flash chromatography
on silica gel
eluting with 1:1 ethyl acetate: hexane to provide the title compound.
EXAMPLE 275B
2-(tetrahydrofuran-3-yloxy)ethanol
EXAMPLE 275A (0.85 g) and 5% palladium on carbon (0.1 g) in ethanol (10 mL)
was treated with a balloon of hydrogen. The reaction was stirred overnight.
The solid was
filtered off, and the filtrate was concentrated to give the title compound.
EXAMPLE 275C
3-nitro-4-(2-(tetrahydrofuran-3-yloxy)ethoxy)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 275B for (tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 275D
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
nitro-4-12-(tetrahydrofuran-3-yloxy)ethoxylphenyllsulfony1)-2-(1H-pyrrolo12,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 275C for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.65 (s,
1H), 8.32 (s, 1H), 8.00-8.02 (m, 2H), 7.49-7.52 (m, 2H), 7.39-7.41 (m, 1H),
7.38 (d, 2H),
7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.33-4.35 (m, 2H),
4.18-4.21 (m,
1H), 3.62-3.67 (m, 4H), 3.09 (s, 4H), 2.83 (s, 2H), 2.26 (s, 2H), 2.15 (s,
2H), 1.96 (s, 2H),
1.85-1.94 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
EXAMPLE 276
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-1(4-
11(trans-4-cyanocyclohexyl)methyllaminol-3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo12,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 276A
trans-4-(aminomethyl)cyclohexanecarbonitrile
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't To a solution of tert-butyl (trans-4-
(cyanomethyl)cyclohexyl)methylcarbamate (500
mg) in dichloromethane (10 mL) was slowly added trifluoroacetic acid (2 mL) at
0 C. The
reaction mixture was warmed to room temperature, stirred for 1 hour and
concentrated to
provide the title compound.
EXAMPLE 276B
4-((tans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (347 mg) and EXAMPLE 276A
(300 mg) in tetrahydrofuran (20 mL) was treated with triethylamine (1.4 mL)
overnight and
concentrated. The residue was triturated with ethyl acetate to provide the
title compound.
EXAMPLE 276C
4-(4- [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en- 1-yllmethyl }piperazin-l-
y1)-N-[(4-
[(trans-4-cyanocyclohexyl)methyl]amino } -3-nitrophenypsulfony1]-2-(1H-
pyrrolo[2,3-
b]pyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
276B in place of EXAMPLE 11B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 8 11.69
(s, 1
H), 11.36 (s, 1 H), 8.60 (t, 1 H), 8.56 (d, 1 H), 8.04 (d, 1 H), 7.79 (dd, 1
H), 7.47 - 7.54 (m, 3
H), 7.34 (d, 2 H), 7.01 - 7.09 (m, 3 H), 6.68 (dd, 1 H), 6.39 (dd, 1 H), 6.19
(d, 1 H), 3.25 (t, 2
H), 3.07 (s, 4 H), 2.76 (s, 2 H), 2.57 - 2.68 (m, 1 H), 2.17 (d, 6 H), 1.92 -
2.06 (m, 4 H), 1.78
(d, 2 H), 1.66 (s, 1 H), 1.35 - 1.53 (m, 4 H), 0.96 - 1.10 (m, 2 H), 0.92 (s,
6 H).
EXAMPLE 277
N-[(5-chloro-6-{ [4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy }pyridin-3-
yl)sulfony11-4-
(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y1)-
2-(1H-
pyrrolo[2,3-b}pyridin-5-yloxy)benzamide
EXAMPLE 277A
methyl 4,4-dimethy1-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was
added 5,5-dimethy1-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at 0 C.
After
stirring for 30 minutes, the mixture was cooled to -78 C and
trifluoromethanesulfonic anhydride (40
mL) was added. The reaction mixture was warmed to room temperature and stirred
for 24
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hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated to
give the product.
EXAMPLE 277B
methyl 2-(4-chloropheny0-4,4-dimethylcyclohex-1-enecarboxylate
EXAMPLE 277A (62.15g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and
tetrakis(triphenylphosphine)palladium(0) (2g) in 2:1 dimethoxyethane /methanol
(600 mL)
were heated to 70 C for 24 hours. The mixture was concentrated. Ether (4x 200
mL) was
added and the mixture was filtered. The combined ether solution was
concentrated to give the
product.
EXAMPLE 277C
(2-(4-chloropheny0-4,4-dimethylcyclohex-1-enyl)methanol
To a mixture of LiBH4 (13g), EXAMPLE 277B (53.8 g) and ether (400 mL), was
added methanol (25 mL) slowly by syringe. The mixture was stirred at room
temperature for
24 hours. The reaction was quenched with 1N HC1 with ice-cooling. The mixture
was diluted
with water and extracted with ether (3x 100 mL). The extracts were dried
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 0-
30% ethyl
acetate/hexanes.
EXAMPLE 277D
tert-butyl 4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-
1-
carboxylate
Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 277C (29.3 g) and
triethylamine (30 mL) in CH2C12 (500 mL) at 0 C, and the mixture was stirred
for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at
room
temperature for 24 hours. The suspension was washed with brine, dried,
(Na2SO4), filtered,
and concentrated. The crude product was chromatographed on silica gel with 10-
20% ethyl
acetate/hexanes.
EXAMPLE 277E
14(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
EXAMPLE 277D (1 g) was stirred in dichloromethane (10 mL), trifluoroacetic
acid
(10 mL), and triethylsilane (1 mL) for 1 hour. The mixture was concentrated,
taken up in a
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mixture of dichloromethane (100 mL) and saturated aqueous Na2CO3 solution (20
mL) and
stirred for 10 minutes. The layers were separated, and the organic layer was
dried over
Na2SO4, filtered, and concentrated to give the product.
EXAMPLE 277F
5-bromo-1-(triisopropylsily0-1H-pyrrolol2,3-blpyridine
To a mixture of 5-bromo-1H-pyrrolol2,3-blpyridine (15.4 g) in tetrahydrofuran
(250
mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and
after 10
minutes, TIPS-C1 (triisopropylchlorosilane ) (18.2 mL) was added. The mixture
was stirred at
room temperature for 24 hours. The reaction was diluted with ether, and the
resulting solution
was washed twice with water. The extracts were dried (Na2SO4), filtered, and
concentrated.
The crude product was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
EXAMPLE 277G
1-(triisopropylsily1)-1H-pyrrolol2,3-blpyridin-5-o1
To a mixture of EXAMPLE 277F (24.3 g) in tetrahydrofuran (500 mL) at -78 C was

added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was
added, and the
mixture was allowed to warm to room temperature over 1 hour. The reaction was
poured into
water, extracted thee times with ethyl acetate, and the combined extracts were
washed with
brine and concentrated. The crude product was taken up in tetrahydrofuran (200
mL) at 0 C,
and 1M NaOH (69 mL) was added, followed by 30% H202 (8.43 mL), and the
solution was
stirred for 1 hour. Na25203 (10 g) was added, and the pH was adjusted to 4-5
with
concentrated HC1 and solid NaH2PO4. The solution was extracted twice with
ethyl acetate,
and the combined extracts were washed with brine, dried (Na2504), filtered,
and
concentrated. The crude product was chromatographed on silica gel with 5-25%
ethyl
acetate/hexanes.
EXAMPLE 277H
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-fluorobenzoate
A mixture of EXAMPLE 277G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and
K3PO4 (9.32 g) in diglyme (40 mL) at 115 C was stirred for 24 hours. The
reaction was
cooled, diluted with ether (600 mL), and washed twice with water, and brine,
and
concentrated. The crude product was chromatographed on silica gel with 2-50%
ethyl
acetate/hexanes.
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EXAMPLE 2771
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y1)benzoate
A mixture of EXAMPLE 277H (1.55 g), EXAMPLE 277E (2.42 g), and HK2PO4
(1.42 g) in dimethylsulfoxide (20 mL) at 135 C was stirred for 24 hours. The
reaction was
cooled, diluted with ether (400 mL), and washed three times with 1M NaOH, and
brine, and
concentrated. The crude product was chromatographed on silica gel with 10-50%
ethyl
acetate/hexanes.
EXAMPLE 277J
2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzoic acid
EXAMPLE 2771(200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 500C was
stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and
extracted thee
times with ethyl acetate. The combined extracts were washed with brine, and
concentrated to
give the pure product.
EXAMPLE 277K
5,6-dichloropyridine-3-sulfonamide
To a solution of 5,6-dichloropyridine-3-sulfonyl chloride (32.16 g) in
isopropyl alcohol (300 mL) at 0 C was added a 30% aqueous solution of NH4OH
(50.8 mL).
After stirring overnight, the solvent was reduced to 1/3 of the original
volume. It was then
partitioned between water and ethyl acetate. The aqueous layer was extracted
with additional
ethyl acetate. The combined organic layers were washed with brine, dried over
MgSO4,
filtered, and concentrated. The residue was chromatographed on silica gel. The
material was
then slurried in 1:9 ethyl acetate/hexanes, filtered and dried under vacuum to
give the title
compound.
EXAMPLE 277L
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) in
tetrahydrofuran (5
mL) was treated with 1.0 N LiA1H4 in tetrahydrofuran (2.54 mL) at 0 C. The
reaction
mixture was stirred at room temperature for 2 hours. Water (0.6 mL) was added
to the
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reaction mixture drop-wise, followed by 2 N aqueous NaOH (0.2 mL). The
reaction was
stirred for another 1 hour. The solid was removed by filtration via a pack of
diatomaceous
earth and washed with ethyl acetate. The filtrate was washed with brine, dried
over MgSO4,
filtered, and concentrated to give the product.
EXAMPLE 277M
tert-butyl 4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-
1-carboxylate
To a solution of EXAMPLE 277L (1 g) in tetrahydrofurab (15 mL) was added NaH
(60% dispersion in mineral oil, 685 mg), and the solution was stirred for 10
minutes.
EXAMPLE 227K (1 g) was added and the reaction stirred for 24 hours. The
mixture was
poured into water, neutralized with 10% HC1, and extracted with ethyl acetate
thee times. The
combined organic layers were washed with brine, dried over MgSO4, filtered,
and
concentrated. The residue was purified with flash column chromatography on
silica gel
eluting with 30% ethyl acetate in hexanes.
EXAMPLE 277N
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide
ditrifluoroacetic acid
EXAMPLE 277M (13 mL) was treated with trifluoroacetic acid (2.363 mL), stirred
at
ambient temperature for 2 hours, concentrated and dried to give the title
compound.
EXAMPLE 2770
5-chloro-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-
sulfonamide
EXAMPLE 277N (0.088 g) and oxetan-3-one (0.014 g) were combined in
dichloromethane (2.0 mL) and dimethylformamide (1.0 mL) and stirred at ambient

temperature for 45 minutes. Sodium triacetoxyborohydride (0.064 g) was added
in portions.
Stirring was continued overnight at ambient temperature. Additional oxetan-3-
one (0.014 g)
was added and stirring was continued for 30 minutes at ambient temperature
before more
sodium triacetoxyborohydride (0.064 g) was added. The reaction mixture was
stirred for 72
hours at ambient temperature, concentrated, chromatographed on silica gel with
0 to 5%
methanol in dichloromethane as the eluent, and dried in a vacuum oven at 80 C
to give the
title compound.
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EXAMPLE 277P
N- 11(5 -chloro-6- { 114-fluoro-1-(oxetan-3-yl)piperidin-4-yllmethoxy }
pyridin-3-yl)sulfonyll -4-
(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 277J (0.063 g), EXAMPLE 2770 (0.042 g), I-ethyl-3-113-
(dimethylamino)propyll-carbodiimide hydrochloride (0.032 g), and 4-
dimethylaminopyridine
(0.027 g) were combined in a 4-mL vial with dichloromethane (1.0 mL) and
stirred overnight
at ambient temperature. The reaction mixture was chromatographed directly
without aqueous
workup on silica gel with 0-4% methanol in dichloromethane as the eluent.
Fractions
containing the desired product were concentrated, slurried in acetonitrile,
concentrated and
dried overnight in a vacuum oven at 80 C to give the title compound. 1H NMR
(500 MHz,
pyridine-d5) 8 13.05 (s, 1H), 9.13 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10
(d, 1H), 7.67 (m,
1H), 7.66 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.51 (m, 2H),
4.63 (m, 4H),
4.53 (d, 2H), 3.39 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.51 (m, 2H), 2.25 (m,
2H), 2.18 (m,
2H), 2.13 (m, 4H), 2.06 (t, 2H), 1.97 (s, 2H), 1.89 (m, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
EXAMPLE 278
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-( { 5-
cyano-6- 112-(tetrahydro-2H-pyran-4-yl)ethoxylpyridin-3-yl} sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 278A
5-bromo-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting 2-(tetrahydro-2H-pyran-4-
yl)ethanol
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 36B.
EXAMPLE 278B
5-cyano-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 278A for EXAMPLE
36B in EXAMPLE 36C.
EXAMPLE 278C
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4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(15-
cyano-6-12-(tetrahydro-2H-pyran-4-yBethoxylpyridin-3-yllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 278B for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.60 (s,
1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.96 (d, 1H), 7.56 (d, 1H), 7.45-7.47 (m,
1H), 7.40 (s, 1H),
7.36 (d, 2H), 7.06 (d, 2H), 6.67 (dd, 1H), 6.34 (dd, 1H), 6.25 (d, 1H), 4.47
(d, 2H), 3.80-3.84
(m, 2H), 3.24-3.28 (m, 2H), 3.12 (s, 2H), 2.16 (s, 2H), 1.97 (s, 2H), 1.61-
1.71 (m, 4H), 1.40
(t, 2H), 1.21-1.25 (m, 2H), 0.93 (s, 6H).
EXAMPLE 279
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-114-(3-
furylmethoxy)-3-nitrophenyllsulfonyll-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
EXAMPLE 279A
4-(furan-3-ylmethoxy)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting furan-3-ylmethanol for
(tetrahydro-
2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 279B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-114-(3-
furylmethoxy)-3-nitrophenyllsulfonyll-2-(1H-pyrrolo12,3-blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 279A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.69 (s,
1H), 8.34 (s, 1H), 8.03-8.06 (m, 2H), 7.83 (s, 1H), 7.69 (t, 1H), 7.51-7.53
(m, 4H), 7.34-7.36
(m, 2H), 7.04-7.06 (m, 2H), 6.68 (dd, 1H), 6.57 (s, 1H), 6.40 (dd, 1H), 6.20
(d, 1H), 5.23 (s,
2H), 3.10 (s, 4H), 2.83 (s, 2H), 2.15-2.32 (m, 6H), 1.39 (t, 2H), 0.92 (s,
6H).
EXAMPLE 280
N-1(5-chloro-6-11(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-
yllmethoxylpyridin-3-
yl)sulfony11-4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-
yllmethyllpiperazin-1-
y1)-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 280A
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(R)-tert-butyl 3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide and (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-
carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 280B
(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 280A for tert-butyl (4-

(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in EXAMPLE 252B.
EXAMPLE 280C
(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting 1,3-difluoropropan-2-one for
4'-
chlorobipheny1-2-carboxaldehyde and EXAMPLE 280B for tert-butyl piperazine-1-
carboxylate in EXAMPLE 1A.
EXAMPLE 280D
N- R5-chloro-6- { R3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yllmethoxy I
pyridin-3-
yl)sulfonyll -4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylc yclohex-l-en-1 -yll
methyl } piperazin-1 -
y1)-2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 280C for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.57 (s, 1 H),
8.38 (d,
1 H), 8.07 (d, 1 H), 7.96 (d, 1 H), 7.57 (d, 1 H), 7.44 (m, 1 H), 7.35 (m, 3
H), 7.05 (d, 2 H),
6.64 (dd, 1 H), 6.33 (dd, 1 H), 6.23 (d, 1 H), 4.65 (d, 2 H), 4.53 (dd, 2 H),
2.92 (m, 8 H), 2.75
(m, 4 H), 2.58 (m, 2 H), 2.20 (m, 6 H), 1.96 (m, 4 H), 1.53 (m, 1 H), 1.39 (t,
2 H), 0.89 (s, 6
H).
EXAMPLE 281
N- R5 -chloro-6- { R3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yllmethoxy I pyridin-
3-yl)sulfonyll -
4-(4- { l2-(4-chloropheny1)-4,4-dimethylc yclohex-1 -en-1 -yllmethyl }
piperazin-l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 281A
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(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 280B for EXAMPLE
261B in EXAMPLE 261C.
EXAMPLE 281B
N- 11(5 -chloro-6- { 11(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yllmethoxy I
pyridin-3-yl)sulfonyll -
4-(4- { 112-(4-chloropheny1)-4,4-dimethylc yclohex-1-en-l-yll methyl }
piperazin-l-y0-2- (1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 281A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.59 (s, 1 H),
8.41 (d,
1 H), 8.10 (d, 1 H), 7.98 (d, 1 H), 7.56 (d, 1 H), 7.46 (m, 1 H), 7.41 (d, 1
H), 7.34 (d, 2 H),
7.04 (d, 2 H), 6.65 (dd, 1 H), 6.35 (dd, 1 H), 6.23 (m, 1 H), 6.03 (m, 1 H),
3.06 (s, 4 H), 2.84
(m, 6 H), 2.63 (m, 4 H), 2.20 (m, 6 H), 1.94 (m, 3 H), 1.53 (m, 1 H), 1.39 (t,
2 H), 0.91 (s, 6
H).
EXAMPLE 282
N-R5-chloro-6- { [1-(1,3-difluoropropan-2-y0-4-fluoropiperidin-4-yllmethoxy }
pyridin-3 -
yl)sulfonyll -4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll
methyl } piperazin-l-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 282A
5-chloro-6-((1-(1,3-difluoropropan-2-y0-4-fluoropiperidin-4-y0methoxy)pyridine-
3-
sulfonamide
EXAMPLE 257B (0.088 g) and 1,3-difluoropropan-2-one (0.028 g) were combined in
dichloromethane (2 mL) and N,N-dimethylformamide (0.500 mL) and stirred at
ambient
temperature for 45 minutes. Sodium triacetoxyborohydride (0.064 g) was added
in portions
and then the reaction mixture was stirred overnight at ambient temperature.
Additional 1,3-
difluoropropan-2-one (0.028 g) was added, followed 30 minutes later by the
addition of more
sodium triacetoxyborohydride (0.064 g). The reaction mixture was stirred at
ambient
temperature for 72 hours. Additional 1,3-difluoropropan-2-one (0.028 g) was
again added,
followed 30 minutes later by the addition of more sodium triacetoxyborohydride
(0.064 g).
The reaction mixture was stirred overnight at ambient temperature. Additional
1,3-
difluoropropan-2-one (0.028 g) was again added, followed 30 minutes later by
the addition of
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more sodium triacetoxyborohydride (0.064 g). The reaction mixture was stirred
overnight at
ambient temperature. The reaction mixture was concentrated under high vacuum
to remove
N,N-dimethylformamide and then chromatographed on silica gel with 0 to 4%
methanol in
CH2C12 as the eluent.
EXAMPLE 282B
N-R5-chloro-6-1 [1-(1,3-difluoropropan-2-y0-4-fluoropiperidin-4-
yllmethoxylpyridin-3-
y0sulfonyll -444-1 [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-
yllmethyllpiperazin-1-
y1)-2-(1H-pyrrolo1L2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 282A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, pyridine-d5) 8 13.05 (s, 1H), 9.12 (t,
1H), 8.72
(d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H),
6.75 (dd, 1H),
6.50 (m, 2H), 4.77 (dd, 1H), 4.65 (dd, 1H), 4.52 (dd, 2H), 3.06 (m, 4H), 2.93
(t, 1H), 2.80 (m,
5H), 2.52 (m, 1H), 2.26 (t, 2H), 2.13 (m, 4H), 2.04 (m, 2H), 1.97 (s, 2H),
1.85 (m, 2H), 1.39
(t, 2H), 1.28 (m, 2H), 0.93 (s, 6H).
EXAMPLE 283
N-(13 -chloro-4- R4-fluoro-1-methylpiperidin-4-y0methoxylphenyllsulfony0-4-(4-
1[2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo 1L2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 283A
3-chloro-4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)benzenesulfonamide
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.265 g) in
tetrahydrofuran (2 mL) was added sodium hydride (0.288 g). After 15 minutes, 3-
chloro-4-
fluorobenzenesulfonamide (0.377 g) was added as a solution in tetrahydrofuran
(1 mL). The
reaction was stirred for 2 hours, quenched with water (5 mL), adjusted to pH-7
with 1N
aqueous HC1, and extracted with dichloromethane (2 x 25 mL). The organic layer
was
washed with brine (25 mL), dried over magnesium sulfate, filtered and
concentrated. Silica
gel chromatography (Reveleris 40 g) eluting with a gradient of 0.1% to 10%
methanol
containing 2N NH3/dichloromethane over 30 minutes gave the title compound.
EXAMPLE 283B
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N-( { 3 -chloro-4- R4-fluoro-1-methylpiperidin-4-yl)methoxylphenyl } sulfonyl)-
4-(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 283A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.60 (s, 1H), 10.68 ¨ 9.84 (m, 1H), 7.99 (d, 1H),
7.79 (d, 1H), 7.63
(t, 1H), 7.54 (d, 1H), 7.50 ¨ 7.38 (m, 2H), 7.34 (d, 2H), 7.04 (d, 3H), 6.64
(dd, 1H), 6.36 (dd,
1H), 6.22 (s, 1H), 4.23 (d, 2H), 3.03 (s, 6H), 2.71 (m, 4H), 2.07 (m, 12H),
1.38 (s, 3H), 1.24
(s, 2H), 0.92 (s, 6H).
EXAMPLE 284
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { [3-
cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyll sulfonyl } -2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 284A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (0.258 g) in
tetrahydrofuran (5
mL) was added sodium hydride (0.355 g) and the reaction stirred at room
temperature for 15
minutes. EXAMPLE 52A (0.400 g) was added and the reaction stirred for an
additional 1
hour. The reaction was poured into ethyl acetate (50 mL) and 1N aqueous HC1
(35 mL). The
organic layer was washed with brine (35 mL) dried over magnesium sulfate,
filtered, and
concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a
gradient of 10% to
100% ethyl acetate/hexanes over 30 minutes gave the title compound.
EXAMPLE 284B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { [3-
cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyll sulfonyl } -2-(1H-pyrrolol2,3-
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 284A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.69 (s, 1H), 11.60 - 11.16 (m, 1H), 8.15 (s, 1H),
8.08 - 8.01 (m,
2H), 7.58 - 7.46 (m, 3H), 7.35 (d, J= 8.4, 2H), 7.29 (d, 1H), 7.04 (d, 2H),
6.68 (d, 1H), 6.40
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(dd, 1H), 6.20 (s, 1H), 4.05 (d, 2H), 3.89 (d, 2H), 3.37 (d, 4H), 3.09 (s,
4H), 2.81 (s, 2H),
2.21 (d, 7H), 1.96 (s, 2H), 1.67 (d, 2H), 1.39 (s, 2H), 0.92 (s, 6H).
EXAMPLE 285
N- 11(5 -chloro-6- { 111-(2,2-difluoroethyl)-4-fluoropiperidin-4-yllmethoxy }
pyridin-3 -
yl)sulfonyl] -4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll
methyl } piperazin-l-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 285A
5-chloro-6-((1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-
sulfonamide
EXAMPLE 257B (0.263 g), 1,1-difluoro-2-iodoethane (0.23 g), and sodium
carbonate
(0.254 g) were combined in a 20-mL vial with N,N-dimethylformamide (6 ml) and
stirred at
70 C overnight. The reaction mixture was concentrated under high vacuum and
then
chromatographed on silica gel with 0 to 5% methanol in CH2C12 as the eluent.
EXAMPLE 285B
N- 11(5 -chloro-6- { 111-(2,2-difluoroethyl)-4-fluoropiperidin-4-yllmethoxy }
pyridin-3 -
yl)sulfonyl] -4-(4- { 112-(4-chloropheny1)-4,4-dimethylc yclohex-l-en-1 -yll
methyl } piperazin-l-
y1)-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 285A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, pyridine-d5) 8 13.05 (s, 1H), 9.12 (d,
1H), 8.72
(d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.43 (m, 2H), 7.06 (m, 2H),
6.75 (dd, 1H),
6.50 (m, 2H), 6.18 (tt, 2H), 4.51 (d, 2H), 3.07 (m, 4H), 2.80 (m, 6H), 2.60
(td, 2H), 2.25 (t,
2H), 2.13 (m, 4H), 2.03 (t, 2H), 1.97 (s, 2H), 1.93 (m, 1H), 1.85 (m, 1H),
1.39 (t, 2H), 0.93
(s, 6H).
EXAMPLE 286
N-( { 3-chloro-4- R4-fluorotetrahydro-2H-pyran-4-yl)methoxylphenyl } sulfony1)-
4-(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 286A
3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
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The title compound was prepared by substituting EXAMPLE 37C for (4-fluoro-1-
methylpiperidin-4-yl)methanol in EXAMPLE 283A.
EXAMPLE 286B
N-(13-chloro-4-1(4-fluorotetrahydro-2H-pyran-4-yl)methoxylphenyllsulfony1)-4-
(4-112-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-l-yllmethyllpiperazin-l-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 286A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.71 (s, 1H), 11.56 - 11.16 (m, 1H), 8.06 (d, 1H),
7.90 (d, 1H), 7.81
(d, 1H), 7.64 - 7.45 (m, 3H), 7.34 (d, 2H), 7.26 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.42 (dd,
1H), 6.18 (s, 1H), 4.28 (d, 2H), 3.78 (d, 2H), 3.61 (dd, 2H), 3.07 (s, 4H),
2.76 (s, 2H), 2.17
(d, 6H), 1.87 (dd, 6H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 287
N-(15-chloro-6-1(4,4-difluorocyclohexyl)methoxylpyridin-3-yllsulfony1)-4-(4-
112-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 287A
(4,4-difluorocyclohexyl)methanol
Ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g, 5.20 mmol) in diethyl ether
(2 mL)
was added dropwise to lithium aluminium hydride (0.24 g) in diethyl ether (15
mL), and
heated under reflux for 4 hours. The reaction was then cooled to 0 C, and
water was added
(0.24 mL), followed by 5N aqueous NaOH (0.24 mL) and water (0.72 mL). Then
Na2SO4 and
more diethyl ether (40 mL) were added, and the mixture was stirred for 30
minutes, then
filtered through celite. After concentration, the residue was diluted with
CH2C12 and Na2SO4
was added, and the mixture was filtered and concentrated to provide the title
compound.
EXAMPLE 287B
5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide and EXAMPLE 287A for (tetrahydro-2H-pyran-4-
yl)methanol in
EXAMPLE 24A.
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EXAMPLE 287C
N-(15-chloro-6-1(4,4-difluorocyclohexyl)methoxylpyridin-3-yllsulfony0-4-(4-112-
(4-
chloropheny0-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 287B for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.63 (s, 1H),
8.46 (d,
1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.56 (d, 1H), 7.47 (m, 2H), 7.35 (d, 2H),
7.03 (d, 2H), 6.66
(dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.25 (d, 2H), 3.07 (br m, 4H), 2.82 (br
s, 2H), 2.30 (br
m, 4H), 2.16 (br m, 2H), 2.00, 1.95, 1.85 (all m, total 9H), 1.40 (t, 2H),
1.37 (m, 2H), 0.92 (s,
6H).
EXAMPLE 288
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyllpiperazin-1-
y1)-N-116-
11141,3 -difluoropropan-2-y0-4-fluoropiperidin-4-yll methoxy1-5 -
(trifluoromethyl)pyridin-3 -
yll sulfony11-2-(1H-pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 288A
5-Nitro-3-(trifluoromethyl)pyridin-2-ol
3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentrated sulfuric
acid (15
mL) at 0 C. The mixture was stirred at 0 C for 5 minutes. To this solution
was added fuming
nitric acid (6 mL) dropwise over 5 minutes. The reaction mixture was stirred
at room
temperature for 2 hours, and then heated at 50 C for 3 hours. After cooling,
the reaction
mixture was poured onto ice (200 g), and the mixture was extracted with ethyl
acetate three
times. The combined organic layers were washed with brine, dried over MgSO4,
filtered, and
concentrated under reduced pressure to provide the title compound.
EXAMPLE 288B
2-Chloro-5-nitro-3-(trifluoromethyl)pyridine
A mixture of EXAMPLE 288A (1.69 g), phosphorus pentachloride (2.03 g), and
phosphoryl trichloride (0.97 mL) was heated at 90 C for 3 hours. After
cooling, the reaction
mixture was poured into ice, and extracted with ethyl acetate three times. The
extract was
washed with brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The
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residue was purified by flash column chromatography on silica gel eluting with
10% ethyl
acetate in hexanes to provide the title compound.
EXAMPLE 288C
6-Chloro-5-(trifluoromethyl)pyridin-3-amine
A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water (40 mL) was
stirred at room temperature for 5 minutes. To this suspension was added
EXAMPLE 288B in
methanol (40 mL). The reaction mixture was stirred at room temperature for 1
hour. More
iron (1.8 g) was added to the reaction mixture, and it was stirred for another
3 hours. The
solid from the reaction mixture was filtered off, and the filtrate was
partitioned between water
and ethyl acetate. The combined organic layers were washed with brine, dried
over MgSO4,
filtered, and concentrated under reduced pressure. The residue was purified by
flash column
chromatography on silica gel eluting with 20% ethyl acetate in hexanes to
provide the title
compound.
EXAMPLE 288D
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20 minutes
to
water (27 mL). The mixture was stirred overnight for 12 hours to give a SO2
containing
solution. Separately, EXAMPLE 288C (1.14 g) in dioxane (5 mL) was added to
concentrated
HC1 (20 mL) at 0 C. The solution was stirred for 5 minutes. To this
suspension/solution was
added sodium nitrite (0.44 g) in water (6 mL) dropwise at 0 C. The solution
was stirred at
0 C for 3 hours. During this time, any solid formed was crushed with a glass
rod to make sure
that EXAMPLE 288C was completely reacted. To the SO2 containing solution was
added
copper(I) chloride (0.115 g). Then, to this solution was added the diazotized
EXAMPLE
288C at 0 C. The solution was stirred for 30 minutes. The reaction mixture was
extracted
with ethyl acetate. The combined organic layers were washed with brine, dried
over MgSO4,
filtered, and concentrated under reduced pressure. The residue was purified by
flash column
chromatography on silica gel eluting with 5% ethyl acetate in hexanes to
provide the title
compound.
EXAMPLE 288E
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide
EXAMPLE 288D (2.03 g) in dioxane (20 mL) solution was cooled to 0 C.
Ammonium hydroxide solution was added dropwise. The reaction mixture was
stirred at 0 C
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for 2 hours followed by room temperature over night. The solvent was partially
removed, and
the residue was partitioned between water and ethyl acetate. The organic phase
was washed
with brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue
was purified by flash column chromatography on silica gel eluting with 0-3%
methanol in
dichloromethane to afford the title compound.
EXAMPLE 288F
tert-butyl 4-fluoro-4-45-sulfamoy1-3-(trifluoromethyl)pyridin-2-
yloxy)methyl)piperidine-1-
carboxylate
The title compound was prepared by substituting EXAMPLE 288E for 4-fluoro-3-
nitrobenzenesulfonamide and EXAMPLE 322A for (tetrahydro-2H-pyran-4-
yl)methanol in
EXAMPLE 24A.
EXAMPLE 288G
6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 288F for tert-butyl (4-

(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in EXAMPLE 252B.
EXAMPLE 288H
6-((1-(1,3-difluoropropan-2-y0-4-fluoropiperidin-4-y0methoxy)-5-
(trifluoromethyl)pyridine-
3-sulfonamide
The title compound was prepared by substituting 1,3-difluoropropan-2-one for
4'-
chlorobipheny1-2-carboxaldehyde and EXAMPLE 288G for tert-butyl piperazine-l-
carboxylate in EXAMPLE 1A.
EXAMPLE 2881
4-(4- { 112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- { [6-
{ 111-(1,3-difluoropropan-2-y0-4-fluoropiperidin-4-yllmethoxy } -5-
(trifluoromethyl)pyridin-3-
y11sulfonyl I -2-(1H-pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 288H for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.50 (s, 1 H),
8.57 (s,
1 H), 8.27 (d, 1 H), 7.91 (d, 1 H), 7.58 (d, 1 H), 7.40 (m, 1 H), 7.35 (d, 2
H), 7.28 (d, 1 H),
7.05 (d, 2 H), 6.61 (dd, 1 H), 6.29 (dd, 1 H), 6.24 (d, 1 H), 4.67 (d, 2 H),
4.55 (d, 2 H), 4.50
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(s, 1 H), 4.44 (s, 1 H), 3.06 (m, 5 H), 2.73 (m, 6 H), 2.19 (d, 6 H), 1.90 (m,
7 H), 1.39 (t, 2 H),
0.93 (s, 6 H).
EXAMPLE 289
4-(4-{ 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(15-
chloro-6-1L2-(tetrahydrofuran-2-y1)ethoxylpyridin-3-y1 I sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 289A
5-chloro-6-(2-(tetrahydrofuran-2-yl)ethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting 2-(tetrahydro-2H-pyran-4-
yl)ethanol
for (tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A in
EXAMPLE 36B.
EXAMPLE 289B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(15-
chloro-6-l2-(tetrahydrofuran-2-y1)ethoxylpyridin-3-y1 I sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 289A for
EXAMPLE 11B in EXAMPLE 11D. 1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.66 (s,
1H), 8.52 (d, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.50-7.55 (m, 3H), 7.35 (d,
2H), 7.05 (d, 2H),
6.68 (dd, 1H), 6.38 (dd, 1H), 6.21 (d, 1H), 4.39-4.51 (m, 4H), 3.87-3.94 (m,
1H), 3.73-3.78
(m, 1H), 3.57-3.62 (m, 1H), 3.11 (s, 4H), 2.89 (s, 2H), 2.33 (s, 4H), 2.15 (s,
2H), 1.77-2.01
(m, 7H), 1.45-1.54 (m, 1H), 1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 290
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } -3-
methylpiperazin-1-y1)-
N-(1 3-nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl I sulfony1)-2-(1H-
pyrrolol2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 290A
2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde
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Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in

dichloromethane (30 mL). The mixture was cooled to -10 C, and phosphoryl
trichloride (4
mL) was added dropwise. The solution was warmed up to room temperature and 3,3-

dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to
reflux
overnight. The reaction mixture was quenched by 0 C solution of sodium acetate
(25 g in 50
mL water). The aqueous layer was extracted with ether (3 x 200 mL). The
organic layers
were combined, dried over Na2SO4, filtered, and dried under vacuum.
EXAMPLE 290B
2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enecarbaldehyde
Into a 1 L round-bottomed flask was added EXAMPLE 290A (6.8 g), 4-
chlorophenylboronic acid (6.5 g) and palladium(II) acetate (0.2 g) in water
(100 mL) to give
a suspension. Potassium carbonate (15 g) and tetrabutylammonium bromide (10 g)
were
added. After degassing after subjecting to vacuum and nitrogen, the mixture
was stirred at
45 C for 4 hours. After filtering through silica gel, diethyl ether (4x 200
mL) was used to
extract the product. The combined organic layers were dried over Na2SO4 and
filtered. The
filtrate was concentrated and purified by flash chromatography on silica with
0-10% ethyl
acetate in hexanes to provide the title compound.
EXAMPLE 290C
tert-butyl 4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)-3-
methylpiperazine-
1-carboxylate
To a solution of tert-butyl 3-methylpiperazine-1-carboxylate (0.256 g) and
EXAMPLE 290B (0.350 g) in dichloromethane (2 mL) was added sodium
triacetoxyborohydride (0.406 g) and the reaction was stirred at room
temperature overnight.
The reaction was quenched with NaHCO3 solution (50 mL) and extracted with
dichloromethane (50 mL). The organic layer was dried over magnesium sulfate,
filtered and
concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a
gradient of 0.5% to
2.5% methanol/dichloromethane gave the title compound.
EXAMPLE 290D
14(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)-2-methylpiperazine
A solution of EXAMPLE 290C (0.298 g) and HC1 (4.0M in dioxane, 2 mL) were
stirred for 1 hour. The reaction was concentrated and partioned between
dichloromethane
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(100 mL) and NaHCO3 (100 mL). The organic layer was washed with brine (50 mL),
dried
over magnesium sulfate, filtered and concentrated to provide the title
compound.
EXAMPLE 290E
methyl 2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(4-42-(4-chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)-3-methylpiperazin-1-y1)benzoate
The title compound was prepared by substituting EXAMPLE 290D for EXAMPLE
3E in EXAMPLE 31.
EXAMPLE 290F
2-(1H-pyrrolo12,3-blpyridin-5-yloxy)-4-(4-42-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)-3-methylpiperazin-1-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 290E for EXAMPLE
15G in EXAMPLE 15H.
EXAMPLE 290G
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1 -en-1 -yll methy11-3-
methylpiperazin-1 -y1)-
N-(13 -nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 290F for EXAMPLE 1E
in EXAMPLE 1G. 1H NMR (300 MHz, dimethylsulfoxide- d6) 6 11.66 (s, 1H), 11.54 -
11.30
(m, 1H), 8.62 - 8.53 (m, 2H), 8.03 (d, 1H), 7.78 (d, 1H), 7.48 (d, 3H), 7.34
(d, 2H), 7.06 (t,
3H), 6.68 (d, 1H), 6.38 (dd, 1H), 6.21 (s, 1H), 3.84 (d, 2H), 3.23 (s, 4H),
2.75 (s, 4H), 1.64 (s,
8H), 1.62 (d, 2H), 1.42 - 1.17 (m, 6H), 0.92 (s, 6H), 0.87 (s, 3H).
EXAMPLE 291
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-
y1)-N-1(4-
113 -(cyclopropylamino)propyll amino1-3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo12,3 -blpyridin-
5-yloxy)benzamide
EXAMPLE 291A
tert-butyl 2-cyanoethyl(cyclopropyl)carbamate
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To a solution of 3-(cyclopropylamino)propanenitrile (5.0g) in tetrahydrofuran
(30
mL) was added di-tert-butyl dicarbonate (9.91g) and a catalytic amount of 4-
dimethylaminopyridine. The mixture was stirred overnight. The mixture was
diluted with
ethyl acetate (400 mL) and washed with 5% aqueous HC1, water and brine. After
drying over
Na2SO4, the mixture was filtered, and the solvent was evaporated under vacuum
to provide
the title compound.
EXAMPLE 291B
tert-butyl 3-aminopropyl(cyclopropyl)carbamate
EXAMPLE 291A (9.75 g) and 7M NH3-methanol (25 mL) were added to a Ra-Ni
2800, water slurry (19.50 g, 332 mmol) in a 250 mL pressure bottle and stirred
for 2 hours at
30 psi and room temperature. The mixture was filtered though a nylon membrane
and
evaporation of the solvent gave the title compound.
EXAMPLE 291C
tert-butyl cyclopropy1(3-(2-nitro-4-sulfamoylphenylamino)propyl)carbamate
To a solution of 4-chloro-3-nitrobenzenesulfonamide (2.5 g), and EXAMPLE 291B
(2.26 g) in dioxane (20 mL) was added N,N-diisopropylethylamine (5 mL). The
mixture was
stirred at reflux overnight. The mixture was diluted with ethyl acetate (400
mL) and washed
with water and brine. After drying over Na2SO4, the mixture was filtered, and
the solvent was
evaporated under vacuum to provide the title compound.
EXAMPLE 291D
tert-butyl 3-(4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoy1)-2-
nitrophenylamino)propyl(cyclopropyl)carbamate
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 291C for EXAMPLE 1F in EXAMPLE 1G.
EXAMPLE 291E
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-l-y1)-N- 11(4-
{ 113-(cyclopropylamino)propyll amino } -3-nitrophenyl)sulfonyll -2-(1H-
pyrrolo [2,3 -blpyridin-
5-yloxy)benzamide
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To a solution of EXAMPLE 291D (2.56 g) in dichloromethane (10 mL) was added
trifluoroacetic acid(10 mL). The mixture was stirred for 2 hours. The mixture
was
concentrated under vacuum and the residue was dissolved in dichloromethane
(300 mL) and
washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. Filtration
and
evaporation of the solvent gave the crude product. The title compound was
obtained by
dissolving 200 mg of the crude material in dimethylsulfoxide/methanol (1:1, 10
mL) and
loaded on Gilson, C18(100A) 250x121.2 mm(10micron), eluting with 30%
acetonitrile to
65% acetonitrile over 40 minutes. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8
11.54 (s, 1
H), 8.43 (m, 2 H), 7.94 (d, 1 H), 7.71 (dd, 1 H), 7.57 (d, 1 H), 7.43 (m, 1
H), 7.34 (m, 3 H),
7.05 (d, 2 H), 6.90 (d, 1 H), 6.63 (dd, 1 H), 6.29 (d, 2 H), 3.43 (m, 2 H),
2.96 (m, 6 H), 2.73
(m, 2 H), 2.22 (m, 7 H), 1.87 (m, 4 H), 1.38 (m, 3 H), 0.94 (m, 6 H), 0.62 (m,
4 H).
EXAMPLE 292
N- { 115-chloro-6-(2-methoxyethoxy)pyridin-3-yll sulfony1}-4-(4- { l2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-en-1-yll methyl}piperazin-l-y1)-2-(1H-pyrrolo 112,3 -
blpyridin-5-
yloxy)benzamide
EXAMPLE 292A
5-chloro-6-(2-methoxyethoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 40A for 4-fluoro-3-
nitrobenzenesulfonamide and 2-methoxyethanol for (tetrahydro-2H-pyran-4-
yl)methanol in
EXAMPLE 24A.
EXAMPLE 292B
N- { 115-chloro-6-(2-methoxyethoxy)pyridin-3-yll sulfony1}-4-(4- { 1L2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-y1)-2-(1H-pyrrolo 112,3 -
blpyridin-5-
yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 292A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.63 (s, 1H),
8.48 (d,
1H), 8.17 (d, 1H), 8.01 (d, 1H), 7.56 (d, 1H), 7.49 (m, 2H), 7.35 (d, 2H),
7.04 (d, 2H), 6.66
(dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.52 (m, 2H), 3.70 (m, 2H), 3.28 (s,
3H), 3.13 (br m,
4H), 2.88 (br s, 2H), 2.34 (br m, 4H), 2.16 (br m, 2H), 1.97 (s, 2H), 1.40 (t,
2H), 0.92 (s, 6H).
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EXAMPLE 293
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1 -yll methyl }
piperazin-1-y1)-N- { [5-
fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yllsulfonyl } -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 293A
The title compound was prepared by substituting 5-bromo-2,3-difluoropyridine
for 4-
fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 293B
tert-butyl 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarbamate

The title compound was prepared by substituting EXAMPLE 293A for EXAMPLE
248A in EXAMPLE 248B.
EXAMPLE 293C
5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl chloride
The title compound was prepared by substituting EXAMPLE 293B for EXAMPLE
248B in EXAMPLE 248C.
EXAMPLE 293D
5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 293C for EXAMPLE
248C in EXAMPLE 248D.
EXAMPLE 293E
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N- { 115-
fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yllsulfonyl } -2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 293D for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400 MHz, pyridine-d5) 8 13.07 (s, 1H), 9.05 (d,
1H), 8.44
(dd, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 7.67 (t, 1H), 7.65 (d, 1H), 7.44 (m,
2H), 7.07 (m, 2H),
6.76 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 4.21 (d, 2H), 3.96 (dd, 2H), 3.31
(td, 2H), 3.07 (m,
4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (m, 3H), 1.58 (dd, 2H),
1.38 (m, 4H), 0.94
(s, 6H).
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EXAMPLE 294
N- 11(3 -chloro-4- { 111-(methoxyacetyl)piperidin-4-yllmethoxy }
phenyl)sulfonyll -4-(4- { 11244-
chloropheny0-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
EXAMPLE 294A
tert-butyl 4-((2-chloro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate
The title compound was prepared by substituting tert-buty1-4-
(hydroxymethyl)piperidine-1-carboxylate for (4-fluoro-1-methylpiperidin-4-
yl)methanol in
EXAMPLE 283A.
EXAMPLE 294B
tert-butyl 4-((4-(N-(2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-
chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperazin-1-y0benzoy0sulfamoy1)-2-
chlorophenoxy)methyl)piperidine-l-carboxylate
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 294A for EXAMPLE 1F in EXAMPLE 1G.
EXAMPLE 294C
2-(1H-pyrrolo112,3-blpyridin-5-yloxy)-N-(3-chloro-4-(piperidin-4-
ylmethoxy)phenylsulfony1)-4-(4-((2-(4-chloropheny1)-4,4-dimethylcyclohex-1-
enyl)methyl)piperazin-1-y1)benzamide
To EXAMPLE 294B (0.286 g) in dichloromethane (3 mL) was added trifluoroacetic
acid (1 mL) and the reaction stirred at room temperature. After 3 hours the
reaction was
concentrated to provide the title compound.
EXAMPLE 294D
N- 11(3 -chloro-4- { 111-(methoxyacetyl)piperidin-4-yllmethoxy }
phenyl)sulfonyll -4-(4- { 11244-
chloropheny0-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5-yloxy)benzamide
To EXAMPLE 294C (0.75 g) as a solution in dichloromethane (1 mL) was added
N,N-diisopropylethylamine (0.055 mL) followed by 2-methoxyacetyl chloride (6
1). After
stirring for 10 minutes the reaction was loaded onto silica gel (Reveleris 40
g) and eluted
using a gradient of 0.5% to 3.5% methanol/dichloromethane over 30 minutes
(flow = 40
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mL/minutes) to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-
d6) 6
11.71 (s, 1H), 11.55 - 11.24 (m, 1H), 8.06 (d, 1H), 7.88 (d, 1H), 7.78 (d,
1H), 7.57 (s, 1H),
7.51 (s, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.21 (d, 1H), 7.04 (d, 2H), 6.67 (d,
1H), 6.42 (dd,
1H), 6.18 (s, 1H), 4.42 - 4.32 (m, 1H), 4.03 (dd, 4H), 3.86 - 3.74 (m, 1H),
3.28 (s, 3H), 3.07
(s, 5H), 2.77 (s, 3H), 2.30 - 1.92 (m, 9H), 1.77 (s, 2H), 1.31 (d, 4H), 0.92
(s, 6H).
EXAMPLE 295
N-R3-chloro-4- { 111-(N,N-dimethylglycyl)piperidin-4-yllmethoxy }
phenyl)sulfonyll -4-(4- { 112-
(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-
(1H-pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting 2-(dimethylamino)acetyl
chloride
for 2-methoxyacetyl chloride in EXAMPLE 294D. 1H NMR (300 MHz,
dimethylsulfoxide-
d6) 6 11.58 (s, 1H), 10.35 ¨ 9.94 (m, 1H), 7.96 (d, 1H), 7.74 (d, 1H), 7.55
(d, 2H), 7.45 (s,
1H), 7.41 ¨ 7.29 (m, 3H), 7.05 (d, 3H), 6.63 (d, 1H), 6.37 ¨ 6.32 (m, 1H),
6.22 (d, 1H), 4.39
(d, 1H), 3.94 (s, 6H), 3.01 (s, 6H), 2.73 (m, 4H), 2.55 (m, 5H), 2.19 (s, 6H),
1.95 (m, 2H),
1.82 (m, 2H), 1.38 (s, 4H), 0.93 (s, 6H).
EXAMPLE 296
4-(4- { l2-(4-chloropheny1)-4,4-dimethylcyclohexyllmethyl } piperidin-l-y1)-N-
( { 3-nitro-4-
Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-pyrrolo112,3-
blpyridin-5-
yloxy)benzamide
EXAMPLE 296A
tert-butyl 4-((4,4-dimethy1-2-oxocyclohexyl)methyl)piperidine-1-carboxylate
3,3-Dimethylcyclohexanone (5.60 mL) was added to sodium
bis(trimethylsilyl)amide
(45.3 mL, 1M in tetrahydrofuran), and the reaction was stirred for 1 hour.
tert-Butyl 4-
(bromomethyl)piperidine-1-carboxylate (11.1 g) in dimethylsulfoxide (30 mL)
was added,
and the reaction was stirred at 50 C for 24 hours. The reaction was cooled,
poured into water
(300 mL), extracted three times with ether, and the combined extracts were
washed three
times with water, and brine, dried over Na2SO4, filtered, and concentrated.
The crude product
was chromatographed on silica gel using 5-20% ethyl acetate in hexanes to
provide the title
compound.
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EXAMPLE 296B
tert-butyl 44(2-(4-chloropheny1)-2-hydroxy-4,4-
dimethylcyclohexyl)methyl)piperidine-l-
carboxylate
(4-Chlorophenyl)magnesium bromide (14.1 mL, 1M in ether) was added to
EXAMPLE 296A (3.25 g) in tetrahydrofuran (40 mL) at -78 C, and the reaction
was stirred
for 20 minutes, and then allowed to warm to room temperature overnight. The
reaction was
quenched with pH 7 buffer (20 mL), extracted with 2x ether, and the combined
extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated. The crude
product was
chromatographed on silica gel using 1-20% ethyl acetate in hexanes to provide
the title
compound.
EXAMPLE 296C
trans-4-42-(4-chloropheny1)-4,4-dimethylcyclohexyl)methyl)piperidine
The title compound was prepared by substituting EXAMPLE 296B for EXAMPLE
1A in EXAMPLE 1B.
EXMAPLE 296D
Trans-methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-

dimethylcyclohexyl)methyl)piperidin-1-y1)benzoate
The title compound was prepared by substituting EXAMPLE 296C for EXAMPLE
263G in EXAMPLE 263H.
EXAMPLE 296E
Trans-2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(4-42-(4-chloropheny1)-4,4-
dimethylcyclohexyl)methyl)piperidin-l-yl)benzoic acid
The title compound was prepared by substituting EXAMPLE 296D for EXAMPLE 31
in EXAMPLE 3J.
EXAMPLE 296F
Trans-4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohexyll methyl } piperidin-
l-y1)-N-( { 3 -
nitro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
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The title compound was prepared by substituting EXAMPLE 296E for EXAMPLE
1E in EXAMPLE 1G. 1H NMR (300MHz, dimethylsulfoxide-d6) 8 11.69 (s, 1H), 11.36
(br s,
1H), 8.60 (t, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.78 (dd, 1H), 7.52 (m, 3H),
7.27 (d, 2H), 7.16
(d, 2H), 7.09 (m, 1H), 6.63 (dd, 1H), 6.38 (dd, 1H), 6.11 (d, 1H), 3.83 (dd,
2H), 3.52 (m, 2H),
3.26 (m, 4H), 2.61 (m, 2H), 2.35 (m, 1H), 1.89 (m, 2H), 1.76 (m, 1H), 1.62 (m,
2H), 1.38 (m,
4H), 1.25 (m, 6H), 1.12 (m, 2H), 0.95 (m, 2H), 0.94 (s, 3H), 0.88 (s, 3H).
EXAMPLE 297
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)-N-{ [6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-
(trifluoromethyl)pyridin-3-yll sulfonyl I benzamide
EXAMPLE 297A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 288E for 4-fluoro-3-
nitrobenzenesulfonamide in EXAMPLE 24A.
EXAMPLE 297B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
l-y1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)-N-{ [6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-
(trifluoromethyl)pyridin-3-yll sulfonyl I benzamide
The title compound was prepared by substituting EXAMPLE 297A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.49 (s, 1 H),
8.56 (d,
1 H), 8.23 (d, 1 H), 7.90 (d, 1 H), 7.58 (d, 1 H), 7.40 (m, 1 H), 7.34 (m, 2
H), 7.26 (d, 1 H),
7.05 (d, 2 H), 6.61 (dd, 1 H), 6.28 (dd, 1 H), 6.24 (d, 1 H), 4.24 (d, 2 H),
3.86 (dd, 2 H), 3.30
(m, 4 H), 3.00 (s, 4 H), 2.73 (s, 2 H), 2.16 (m, 6 H), 1.97 (m, 2 H), 1.61
(dd, 2 H), 1.33 (m, 4
H), 0.93 (s, 6 H).
EXAMPLE 298
N-( 15-chloro-6- Rtrans-4-hydroxycyclohexyl)methoxylpyridin-3-yll sulfonyl)-4-
(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
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EXAMPLE 298A
6-((trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-5-chloropyridine-3-
sulfonamide
The title compound was prepared by substituting (trans-4-(tert-
butyldimethylsilyloxy)cyclohexyl)methanol for (tetrahydro-2H-pyran-4-
yl)methanol and
EXAMPLE 40A for EXAMPLE 36A in EXAMPLE 36B.
EXAMPLE 298B
N-(15-chloro-6- Rtrans-4-hydroxycyclohexyl)methoxylpyridin-3-yllsulfony1)-4-(4-
1 [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyllpiperazin-l-y1)-2-(1H-
pyrrolo 1L2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 298A for
EXAMPLE 11B in EXAMPLE 11D. After the reaction was over, the solvent was
removed,
and the residue was treated with 1:1 trifluoroacetic acid/dichloromethane for
two hours. The
solvents were removed, and the residue was purified by reverse phase Gilson
Prep HPLC
system with a Phenomenex prep column (Luna, 5 n, C18(2), 250X21.20 mm, 5 A)
eluting
with 20-80% acetonitrle in water with 0.1% trifluoroacetic acid to provide the
title
compound.1H NMR (500MHz, dimethylsulfoxide-d6) 8 11.65 (s, 1H), 8.47 (s, 1H),
8.15 (s,
1H), 8.01 (d, 1H), 7.54 (d, 1H), 7.48-7.49 (m, 1H), 7.35 (d, 2H), 7.05 (d,
2H), 6.67 (dd, 1H),
6.37 (d, 1H), 6.21 (s, 1H), 4.53 (t, 1H), 4.18 (d, 2H), 3.08 (s, 4H), 2.84 (s,
2H), 2.29 (s, 4H),
2.15 (s, 2H), 1.96 (s, 2H), 1.79-1.83 (m, 5H), 1.39 (t, 2H), 1.08-1.13 (m,
5H), 0.93 (s, 6H).
EXAMPLE 299
4-(4-1 [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(13-
cyano-4-R4-fluorotetrahydro-2H-pyran-4-y1)methoxylphenyllsulfony1)-2-(1H-
pyrrolo 1L2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 299A
3-cyano-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
The title compound was prepared by substituting EXAMPLE 37C for (tetrahydro-2H-

pyran-4-yl)methanol in EXAMPLE 284A.
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EXAMPLE 299B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl}piperazin-1-
y1)-N-(13-
cyano-4-R4-fluorotetrahydro-2H-pyran-4-y1)methoxylphenyl I sulfony1)-2-(1H-
pyrrolo [2,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 299A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.72 (s, 1H), 10.24 - 9.27 (m, 1H), 8.21 (d, 1H),
8.12 (dd, 1H), 8.05
(d, 1H), 7.63 - 7.46 (m, 3H), 7.45 - 7.31 (m, 3H), 7.07 (d, 2H), 6.70 (dd,
1H), 6.42 (s, 1H),
6.23 (s, 1H), 4.38 (d, 2H), 3.91 - 3.73 (m, 2H), 3.68 - 3.51 (m, 2H), 3.22 -
2.96 (m, 10H),
2.31 - 2.12 (m, 2H), 1.99 (s, 6H), 1.43 (t, 2H), 0.93 (s, 6H).
EXAMPLE 300
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-1-
y1)-N-({ 6-
Rtrans-4-methoxycyclohexyl)methoxyl -5 -(trifluoromethyl)pyridin-3 -yl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 300A
6-((trans-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-
sulfonamide
The title compound was prepared by substituting EXAMPLE 288E for 4-fluoro-3-
nitrobenzenesulfonamide and EXAMPLE 121A for (tetrahydro-2H-pyran-4-
yl)methanol in
EXAMPLE 24A.
EXAMPLE 300B
4-(4-{ [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl }piperazin-1-
y1)-N-({ 6-
Rtrans-4-methoxycyclohexyl)methoxyl -5 -(trifluoromethyl)pyridin-3 -yl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 300A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.50 (s, 1 H),
8.56 (d,
1 H), 8.23 (d, 1 H), 7.90 (d, 1 H), 7.58 (d, 1 H), 7.40 (m, 1 H), 7.35 (d, 2
H), 7.27 (d, 1 H),
7.05 (dõ 2 H), 6.61 (dd, 1 H), 6.28 (dd, 1 H), 6.24 (d, 1 H), 4.20 (d, 2 H),
3.23 (s, 3 H), 3.03
(m, 5 H), 2.73 (s, 2 H), 2.18 (m, 6 H), 1.98 (m, 5 H), 1.80 (m, 3 H), 1.39 (t,
2 H), 1.09 (m, 4
H), 0.93 (s, 6 H).
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EXAMPLE 301
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(16-
1(cis-4-methoxycyclohexyl)methoxyl -5- (trifluoromethyl)pyridin-3 -
yllsulfony1)-2-(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 301A
6-((cis-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 288E for 4-fluoro-3-
nitrobenzenesulfonamide and EXAMPLE 121A for (tetrahydro-2H-pyran-4-
yl)methanol in
EXAMPLE 24A.
EXAMPLE 301B
4-(4-112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-
y1)-N-(16-
1(cis-4-methoxycyclohexyl)methoxyl -5- (trifluoromethyl)pyridin-3 -
yllsulfony1)-2-(1H-
pyrrolo12,3b1pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 301A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.49 (m, 1 H),
8.54
(m, 1 H), 8.23 (d, 1 H), 7.91 (d, 1 H), 7.59 (d, 1 H), 7.40 (m, 1 H), 7.34 (m,
2 H), 7.27 (d, 1
H), 7.04 (d, 2 H), 6.61 (dd, 1 H), 6.29 (dd, 1 H), 6.24 (d, 1 H), 4.20 (d, 2
H), 3.37 (m, 2 H),
3.19 (s, 3 H), 3.00 (s, 4 H), 2.73 (s, 2 H), 2.18 (m, 6 H), 1.96 (s, 2 H),
1.80 (m, 3 H), 1.50 (dd,
2 H), 1.37 (m, 6 H), 0.93 (s, 6 H).
EXAMPLE 302
N-(15-chloro-6-1(4,4-difluoro-1-hydroxycyclohexyl)methoxylpyridin-3-
yllsulfony1)-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperidin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
EXAMPLE 302A
44(2-(4-chloropheny1)-4,4-dimethylcyclohex-1-enyl)methyl)piperidine
EXAMPLE 296B (1.0 g) was stirred in dichloromethane (15 mL) and
trifluoroacetic
acid (15 mL) at 35 C for 48 hours. The mixture was concentrated, taken up in
dichloromethane (100 mL), and stirred, and saturated Na2CO3 solution (20 mL)
was added
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slowly. The solution was separated and the organic layer was dried over
Na2SO4, filtered, and
concentrated to provide the title compound.
EXAMPLE 302B
methyl 2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-enyl)methyl)piperidin-l-y1)benzoate
The title compound was prepared by substituting EXAMPLE 302A for
EXAMPLE 263G in EXAMPLE 263H.
EXAMPLE 302C
2-(1H-pyrrolol2,3-blpyridin-5-yloxy)-4-(44(2-(4-chloropheny1)-4,4-
dimethylcyclohex-1-
enyl)methyl)piperidin-1-y1)benzoic acid
The title compound was prepared by substituting EXAMPLE 302B for EXAMPLE 31
in EXAMPLE 3J.
EXAMPLE 302D
1,1-difluoro4-methylenecyclohexane
Butyllithium (12.32 mL, 2.5 M solution in hexanes) was added to a solution of
methyltriphenylphosphonium chloride (9.63 g) in tetrahydrofuran (50 mL) at 0
C, and the
reaction was stirred for 5 minutes. 4,4-Difluorocycleohexanone (3.76 g) in
dioxane (150
mL)was then added, and the reaction was stirred for 30 minutes. Water (3 mL)
was added,
and then hexane (150 mL) was slowly added, the reaction was filtered, and the
solution
carried on.
EXAMPLE 302E
4,4-difluoro-1-(hydroxymethyl)cyclohexanol
To the solution from EXAMPLE 302D was added water (75 mL), then N-
metthylmorpholine-N-oxide (6.4 mL, 50% solution in water) and 0s04 (14.2 g,
2.5 wt %
solution in tert-butanol) were added, and the reaction was stirred for 96
hours at 50 C. The
solution was cooled to room temperature, treated with saturated aqueous
Na2S203 solution
(100 mL) for 30 minutes, and then acidified with concentrated aqueous HC1. The
solution
was then extracted three times with ethyl acetate, and the organic layers were
combined,
washed with 1M HC1, and brine, and concentrated. The crude mixture was
chromatographed
on silica gel using 10-100% ethyl acetate in hexanes, and then 5% methanol in
ethyl acetate
to give the product.
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EXAMPLE 302F
5-chloro-6-((4,4-difluoro-1-hydroxycyclohexyl)methoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 302E for tetrahydro-2H-
pyran-4-yl)methanol and EXAMPLE 40A for 4-fluoro-3-nitrobenzenesulfonamide in
EXAMPLE 24A.
EXAMPLE 302G
N-(15-chloro-6-1(4,4-difluoro-1-hydroxycyclohexyl)methoxylpyridin-3-
yllsulfony1)-4-(4-
112-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperidin-1-y1)-2-
(1H-
pyrrolo12,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 302C for EXAMPLE
1E and EXAMPLE 302F for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300MHz,
dimethylsulfoxide-d6) 8 11.65 (br s, 2H), 8.51 (s, 1H), 8.18 (s, 1H), 8.02 (d,
1H), 7.53 (m,
3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.69 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H),
4.88 (s, 1H), 4.27
(s, 2H), 3.10 (m, 4H), 2.88 (m, 1H), 2.33 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H),
1.91 (m, 2H),
1.73 (m, 4H), 1.52 (m, 1H), 1.40 (m, 2H), 1.31 (m, 1H), 0.93 (s, 3H), 0.91 (m,
2H).
EXAMPLE 303
N-1(3-chloro-4-11trans-4-(morpholin-4-yl)cyclohexyllmethoxylphenyl)sulfonyll -
444-11244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 303A
trans-4-morpholinocyclohexyl)methanol
To tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (0.500 g) was added
hydrogen chloride (4.0M in dioxane, 2.2 mL) and the reaction was stirred for 1
hour and
concentrated. The resulting solid was dissolved in acetonitrile (4 mL) and
treated with N,N-
diisopropylethylamine (1.523 mL) followed by 1-bromo-2-(2-bromoethoxy)ethane
(0.556 g)
and heated to 60 C. After stirring overnight the reaction was concentrated,
loaded onto silica
gel (Reveleris 40 g) and eluted using a gradient of 1% to 10%
methanol/dichloromethane
over 30 minutes (flow = 40 mL/min) to provide the title compound.
EXAMPLE 303B
3-chloro-4-(((lr,4r)-4-morpholinocyclohexyl)methoxy)benzenesulfonamide
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The title compound was prepared by substituting EXAMPLE 303A for (4-fluoro-1-
methylpiperidin-4-yl)methanol in EXAMPLE 283A.
EXAMPLE 303C
N- [(3-chloro-4- { [trans-4-(morpholin-4-yOcyclohexyl[methoxy}phenyOsulfonyll-
4-(4- { [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo [2,3 -
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 303B for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide- d6) 6 11.65 (s, 1H), 10.96 ¨ 10.59 (m, 1H), 8.02 (d, 1H),
7.82 (d, 1H),
7.69 (s, 1H), 7.50 (dd, 3H), 7.38 ¨ 7.30 (m, 2H), 7.15 ¨ 6.99 (m, 3H), 6.65
(dd, 1H), 6.39 (dd,
1H), 6.20 (d, 1H), 3.91 (d, 2H), 3.64 (s, 4H), 3.04 (s, 4H), 2.73 (s, 7H),
2.18 (s, 6H), 1.93 (m,
6H), 1.80 ¨ 1.65 (m, 1H), 1.32 (m, 6H), 0.92 (s, 6H).
EXAMPLE 304
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 3- [cyclopropy1(1,3-thiazol-5-ylmethyl)amino[propyl}amino)-3-
nitrophenyllsulfonyll-2-
(1H-pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
To a solution of EXAMPLE 291E (95 mg) in dichloromethane (2 mL) and acetic
acid
(0.5 mL) was added thiazole-5-carbaldehyde (13 mg) followed by sodium
triacetoxyborohydride (35 mg). The mixture was stirred overnight. The mixture
was diluted
with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, and brine
and
dried over Na2SO4. Filtration and evaporation of the solvent gave crude
product which was
dissolved in dimethylsulfoxide/methanol (6 mL, 1:1) and loaded on Gilson,
C18(100A)
250x121.2 mm(10micron), with 30% acetonitrile to 65% acetonitrile over 40
minutes. 1H
NMR (300 MHz, dimethylsulfoxide-d6) 8 11.67 (s, 1 H), 8.95 (s, 1 H), 8.57 (m,
2 H), 8.03
(d, 1 H), 7.78 (m, 2 H), 7.49 (m, 3 H), 7.35 (m, 2 H), 7.02 (m, 3 H), 6.67
(dd, 1 H), 6.38 (dd,
1 H), 6.19 (d, 1 H), 4.00 (s, 2 H), 3.05 (d, 4 H), 2.73 (m, 2 H), 2.60 (m, 2
H), 2.18 (m, 7 H),
1.95 (s, 2 H), 1.79 (m, 3 H), 1.37 (m, 3 H), 0.92 (s, 6 H), 0.45 (m, 4 H).
EXAMPLE 305
N-({ 3 -chloro-4- [(trans -4-hydroxyc yclohexyl)methoxylphenyl}sulfony1)-4-(4-
{ [2-(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-y1)-2-(1H-
pyrrolo [2,3 -
b[pyridin-5-yloxy)benzamide
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EXAMPLE 305A
3-chloro-4-((trans-4-hydroxycyclohexyl)methoxy)benzenesulfonamide
(Trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (275 mg, prepared
according to a procedures in WO 2008/124878) and 3-chloro-4-
fluorobenzenesulfonamide
(259 mg) in tetrahydrofuran (15 mL) were treated with sodium hydride (180 mg,
60%)
overnight. The reaction was quenched with water (1 mL) and trifluoroacetic
acid (4 mL) was
added. The resulting mixture was stirred for 1 hour and concentrated. The
residue was
triturated with water and methanol to provide the title compound.
EXAMPLE 305B
N-(13 -chloro-4- Rtrans-4-hydroxycyclohexyl)methoxylphenyllsulfony1)-4-(4-112-
(4-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyllpiperazin-1-y1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 11D using EXAMPLE
305A in place of EXAMPLE 11B. 1H NMR (500 MHz, dimethylsulfoxide-d 6) 8 11.71
(s, 1
H), 11.38 (s, 1 H), 8.06 (d, 1 H), 7.87 (d, 1 H), 7.76 (dd, 1 H), 7.57 (d, 1
H), 7.51 - 7.55 (m, 1
H), 7.49 (d, 1 H), 7.34 (d, 2 H), 7.18 (d, 1 H), 7.04 (d, 2 H), 6.67 (dd, 1
H), 6.42 (dd, 1 H),
6.18 (d, 1 H), 4.54 (d, 1 H), 3.91 (d, 2 H), 3.07 (s, 4 H), 2.75 (s, 2 H),
2.17 (d, 6 H), 1.95 (s, 2
H), 1.78 - 1.90 (m, 4 H), 1.63 - 1.75 (m, 1 H), 1.38 (t, 2 H), 1.00 - 1.25 (m,
4 H), 0.92 (s, 6
H).
EXAMPLE 306
4- (4-112-(4-chloropheny1)-4,4-dimethylcyclohex-l-en-1 -yll methyllpiperazin-1-
y1)-N-(13-
chloro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyllsulfony1)-2-(1H-
pyrrolo12,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 306A
3-chloro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
chlorobenzenesulfonamide for 4-chloro-3-nitrobenzenesulfonamide, (tetrahydro-
2H-pyran-4-
yl)methanamine for 4-methylpiperazin-1-amine dihydrochloride and Hunig's base
for
N1,N1,N2,N2-tetramethylethane-1,2-diamine in EXAMPLE 6A.
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EXAMPLE 306B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yllmethyl } piperazin-
1-y1)-N-( { 3-
chloro-4- Rtetrahydro-2H-pyran-4-ylmethyl)aminolphenyl } sulfony1)-2-(1H-
pyrrolo [2,3 -
blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 306A for EXAMPLE
11B in EXAMPLE 11D. 1H NMR (400MHz, dimethylsulfoxide-d6) 8 11.80 (s, 1H),
11.17
(br s, 1H), 8.09 (d, 1H), 7.71 (d, 1H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.53 (dd,
1H), 7.50 (d, 1H),
7.34 (d, 2H), 7.03 (d, 2H), 6.74 (d, 1H), 6.66 (dd, 1H), 6.42 (m, 1H), 6.40
(t, 1H), 6.16 (d,
1H), 3.83 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 3.06 (br m, 4H), 2.72 (s, 2H),
2.17 (br m, 6H),
1.95 (s, 2H), 1.83 (m, 1H), 1.59 (br m, 2H), 1.38 (t, 2H), 1.20 (ddd, 2H),
0.92 (s, 6H).
EXAMPLE 307
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl-3-(trifluoromethyl)phenyl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
EXAMPLE 307A
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-
(trifluoromethyl)benzenesulfonamide
The title compound was prepared by substituting 4-fluoro-3-
(trifluoromethyl)benzenesulfonamide for 4-fluoro-3-nitrobenzenesulfonamide and

EXAMPLE 37C for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.
EXAMPLE 307B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-
1-y1)-N-( { 4-
R4-fluorotetrahydro-2H-pyran-4-yl)methoxyl -3-(trifluoromethyl)phenyl I
sulfony1)-2-(1H-
pyrrolol2,3-blpyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 307A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400 MHz, pyridine-
d5) 8 13.07 (s, 1H), 8.78 (d, 1H), 8.58 (dd, 1H), 8.42 (d, 1H), 8.09 (d, 1H),
7.67 (t, 1H), 7.65
(d, 1H), 7.43 (m, 2H), 7.16 (d, 1H), 7.06 (m, 2H), 6.74 (dd, 1H), 6.51 (m,
2H), 4.21 (d, 2H),
3.87 (m, 2H), 3.78 (td, 2H), 3.06 (m, 4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.13
(m, 4H), 1.95 (m,
6H), 1.39 (t, 2H), 0.93 (s, 6H).
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EXAMPLE 308
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yfl methyl}piperazin-
1-y1)-N- { [4-
( { 3- [cyclopropy1(2,2,2-trifluoroethyl)amino[propyl}amino)-3-nitrophenyfl
sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 308A
4-(3-(cyclopropylamino)propylamino)-3-nitrobenzenesulfonamide
To a solution of EXAMPLE 291C (4.14 g) in dichloromethane (10 mL) was added
trifluoroacetic acid(10 mL). The mixture was stirred for 2 hours. The mixture
was
concentrated under vacuum and the residue was dissolved in dichloromethane
(300 mL) and
washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. Filtration
and
evaporation of solvent gave the title compound.
EXAMPLE 308B
4-(3-(cyclopropy1(2,2,2-trifluoroethyl)amino)propylamino)-3-
nitrobenzenesulfonamide
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (6 mL) was added
2,2,2-trifluoroethyl trifluoromethanesulfonate (255 mg) and N,N-
diisopropylethylamine (258
mg). The mixture was stirred overnight. The mixture was diluted with
dichloromethane (300
mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4.
Filtration and
evaporation of solvent gave the title compound.
EXAMPLE 308C
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yfl methyl}piperazin-1-
y1)-N- { [4-
( { 3- [cyclopropy1(2,2,2-trifluoroethyl)amino[propyl}amino)-3-nitrophenyfl
sulfony11-2-(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 308B for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (300 MHz,
dimethylsulfoxide-d6) 8 11.67 (s, 1 H), 11.38 (m, 1 H), 8.55 (d, 2 H), 8.03
(d, 1 H), 7.81 (dd,
1 H), 7.50 (m, 3 H), 7.34 (d, 2 H), 7.05 (m, 3 H), 6.67 (dd, 1 H), 6.38 (dd, 1
H), 6.19 (d, 1 H),
3.07 (m, 4 H), 2.82 (m, 4 H), 2.18 (m, 7 H), 1.38 (m, 2 H), 0.92 (s, 6 H),
0.44 (m, 4 H).
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EXAMPLE 309
N- 11(3-chloro-4- { t1-(oxetan-3 -yl)piperidin-4-yll methoxy }
phenyl)sulfonyll -4-(4- { [244-
chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl } piperazin-l-y1)-2-(1H-
pyrrolo 112,3 -
blpyridin-5 -yloxy)benzamide
To a solution of EXAMPLE 294B (0.150 g) in dichloromethane (2 mL) was added
trifluoroacetic acid (1 mL). After stirring for 1 hour the reaction was
concentrated and dried
under high vacuum. The residue was dissolved in dichloromethane (2 mL) and
treated with
sodium triacetoxyborohydride (0.050 g) and oxetan-3-one (0.017 g) and stirred
overnight at
room temperature. The reaction was quenched with saturated aqueous NaHCO3 (20
mL) and
extracted into dichloromethane (50 mL). The organic layer was separated,
washed with brine
(25 mL), dried over Na2SO4, filtered, and concentrated. Silica gel
chromatography (Reveleris
40 g) eluting with a gradient of 0.5% to 5% methanol/dichloromethane over 30
minutes (flow
= 40 mL/min) provided the title compound. 1H NMR (300 MHz, dimethylsulfoxide-
d6) 6
11.70 (s, 1H), 11.21 (s, 1H), 8.05 (d, 1H), 7.87 (d1H), 7.75 (dd, 1H), 7.61 -
7.42 (m, 3H),
7.42 - 7.26 (m, 2H), 7.18 (d, 1H), 7.14 - 6.97 (m, 2H), 6.67 (dd, 1H), 6.41
(dd, 1H), 6.18 (d,
1H), 4.51 (dt, 4H), 3.99 (d, 2H), 3.56 - 3.32 (m, 1H), 3.06 (s, 4H), 2.89 -
2.68 (m, 4H), 2.16
(d, 6H), 2.01 - 1.69 (m, 7H), 1.50 - 1.07 (m, 4H), 0.92 (s, 6H).
EXAMPLE 310
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yll methyl }
piperazin-1-y1)-N-(1 3,5-
difluoro-4- 11(4-fluorotetrahydro-2H-pyran-4-yl)methoxylphenyl I sulfony1)-2-
(1H-pyrrolo t2,3-
blpyridin-5-yloxy)benzamide
EXAMPLE 310A
3,5-difluoro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
EXAMPLE 37C (0.423 g) in tetrahydrofuran (30 mL) was treated with NaH (60% oil

dispersion) (0.480 g), stirred 20 minutes at ambient temperature, treated with
3,4,5-
trifluorobenzenesulfonamide (0.633 g) and stirred 30 minutes. N,N-
Dimethylacetamide (15
mL) was added to increase solubility of the reactants and stirring was
continued overnight at
ambient temperature. Additional NaH (60% oil dispersion) (0.480 g) and N,N-
dimethylacetamide (15 mL) were added and the mixture was heated overnight at
50 C. The
reaction was quenched with saturated aqueous NH4C1 solution and then
partitioned between
saturated aqueous NH4C1 solution and ethyl acetate. The organic layer was
washed with
water and brine, dried (MgSO4), filtered and concentrated. The concentrate was
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chromatographed on amine functionalized silica gel with 0 to 2% methanol in
CH2C12 as the
eluent. The residue was further purified by reverse phase HPLC on a C18 column
using a
gradient of 10-70% acetonitrile/0.1% trifluoroacetic acid in water to provide
the title
compound.
EXAMPLE 310B
4-(4- { 1L2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N-({ 3,5-
difluoro-4- [(4-fluorotetrahydro-2H-pyran-4-yl)methoxy[phenyl}sulfony1)-2-(1H-
pyrrolo [2,3-
b[pyridin-5-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE 1E
and EXAMPLE 310A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (500 MHz, pyridine-
d5) 8 13.06 (s, 1H), 8.41 (d, 1H), 8.11 (m, 2H), 8.08 (d, 1H), 7.66 (m, 2H),
7.44 (m, 2H), 7.07
(m, 2H), 6.75 (dd, 1H), 6.52 (d, 1H), 6.50 (dd, 1H), 4.26 (d, 2H), 3.85 (dd,
1H), 3.83 (dd,
1H), 3.74 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.14 (m, 4H),
1.97 (s, 2H), 1.87
(m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).
EXAMPLE 311
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 3- [cyclopropyl(oxetan-3-yl)amino[propyl}amino)-3 -nitrophenyl[sulfony11-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
EXAMPLE 311A
4-(3-(cyclopropyl(oxetan-3-yl)amino)propylamino)-3-nitrobenzenesulfonamide
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) was added
oxetan-3-one (72 mg) followed by sodium triacetoxyborohydride (318 mg). The
mixture was
stirred overnight. The mixture was diluted with dichloromethane (300 mL) and
washed with
aqueous NaHCO3, water and brine and dried over Na2SO4. After filtration,
evaporation of the
solvent gave the crude title compound.
EXAMPLE 311B
4-(4- { [2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-1-yl[methyl}piperazin-1-
y1)-N- { [4-
( { 3- [cyclopropyl(oxetan-3-yl)amino[propyl}amino)-3-nitrophenyl[sulfony11-2-
(1H-
pyrrolo[2,3-b[pyridin-5-yloxy)benzamide
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